JPH05213852A - Azoxy group-containing compound - Google Patents

Abstract

PURPOSE:To provide a novel compound useful as an antimycotic agent for medical, veterinary and agri- and horticultural purposes. CONSTITUTION:A compound of formula I (R1, R2 are H, lower alkyl, lower alkenyl, lower alkinyl, lower alkoxy, aryl, aralkyl; R3 is H, lower alkyl, benzoyl; when R1 is n-butyl, R3 is halogenated lower-alkyl), for example, 2- hydroxyimino-3-[2-(4-(3-iodopropargyl)oxyphenyl)-1-propenyl-ONN-azoxy] -butane. The compound of formula I is obtained by allowing an acid to act on a compound of formula II (n is 2, 3) such as hydrochloric acid followed by reaction of the product with a compound of the formula: H2N-OR3 in the presence of a base such as sodium carbonate in a solvent such as THR at -10 deg.C to the refluxing temperature. It is useful against molds infectious to warm-blood animal such as Candida, Cryptococcus, Aspergillus or the like and infectious to cropping plants in agriculture and horticulture such as piricularia, botrytis or saccharomyces.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel azoxy group-containing compound, and more particularly to an antifungal compound and an antifungal agent containing this compound as an active ingredient.

[0002]

2. Description of the Related Art The present inventors have previously found that Streptomyces s. p.
It was found that KC-7367 (FERM BP-1277) produces a substance exhibiting a strong antibacterial activity against fungi, and further two antifungal substances KA-73 were produced from the culture solution.
67A (Maniwamycin A) and KA-7366B (Maniwamycin B) were isolated and identified (JP-A-1-624).
(See No. 8). The antifungal substances KA-7366A and KA-7366B are represented by the following formula.

[Chemical 2] X = -CO-: KA-7366A X = -CH (OH)-: KA-7366B

Further, the present inventors have confirmed that a 2-imino compound obtained by iminating the carbonyl group at the 2-position of KA-7367A as a raw material exhibits excellent antifungal activity, and applied for a patent ( PCT / JP89 / 01
082). However, although these compounds show excellent antifungal activity and stability, in order to apply them to the treatment of dermatomycosis such as tinea pedis, compounds with better anti-tinetosis activity are needed. .. Further, in order to obtain a better antifungal agent, it is necessary to synthesize various derivatives. However, synthesizing KA-7366 produced by a fermentation method as a raw material is limited to the productivity of the raw material and the kind of the derivative. There is a drawback that there is.

[0004]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the inventors of the present invention used the organic synthesis method KA-7367.
The organic synthesis method of A was completed, and its analogs were further synthesized. They found that they were useful as antifungal agents, and completed the present invention. The present invention has the general formula

[Chemical 3] [Wherein R ₁ and R ₂ are the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group (which may be substituted with a halogen atom), a lower alkoxy group, a lower alkenyloxy group, a lower alkynyl group. An oxy group (which may be substituted with a halogen atom), an aryl group or an aralkyl group (the aryl group and the aralkyl group are 1
To two halogen atoms, a lower alkyl group, a lower alkoxy group, a halogenated lower alkynyl group or a halogenated lower alkynyloxy group),
R ₃ is a hydrogen atom, a lower alkyl group (which may be substituted with a carboxyl group), a lower alkynyl group (which may be substituted with a halogen atom), a lower alkynyloxy group (which may be substituted with a halogen atom) ), A benzoyl group (which may be substituted with a halogenated lower alkynyloxy group), but when R ₁ represents an n-butyl group, R ₃ is substituted with a halogenated lower alkynyl group or a halogenated alkynyloxy group. Represents a benzoyl group represented by the formula [1].

The lower alkyl group, lower alkenyl group and lower alkynyl group for each substituent of the compound of formula I are preferably linear or branched ones having 1 to 8 carbon atoms. As a halogen atom, a fluorine atom, a chlorine atom,
Iodine atom and the like are preferable. There are anti-isomers and syn-isomers of the oxime hydroxyl group in the compound of formula I, both of which have antifungal activity and belong to the scope of the present invention.

The compound (I) of the present invention has the general formula

[Chemical 4] (In the formula, R ₁ and R ₂ have the above-mentioned meanings, and n is 2 or 3.) An acid is allowed to act on the compound represented by the general formula

[Chemical 5] A compound of the general formula H ₂ N—OR ₃ (IV), in which R ₃ has the abovementioned meaning, is obtained. It can be produced by reacting the represented compound. The compound of formula III has the general formula

[Chemical 6] It can be produced by dehydrating a compound represented by the formula (each symbol in the formula has the above meaning) to introduce a carbon-carbon double bond.

The compound of formula V has the general formula

[Chemical 7] (Wherein the symbols in the formula have the above meanings), a compound represented by the general formula

[Chemical 8] It can be produced by reacting with a ketone or aldehyde represented by the formula (each symbol in the formula has the above meaning).

The reaction is represented by the following formula.

[Chemical 9]

The compound (VI) is obtained by reacting the compound (VI) with the compound (VII). This reaction is preferably carried out after activating the carbon atom of the methyl group bonded to the azoxy group of compound (VI) using a strong base. Examples of the base include lithium diisopropylamide, lithium hexamethyldisilazide, sodium hydride and the like. For example, when lithium diisopropylamide is used as the base, the compound (VI) is reacted with the newly prepared base in a solvent at −70 ° C. to + 50 ° C. for several minutes to several hours to react with the methyl of the compound (VI). The carbon atom of the group is activated, and 1 to 5 mol of the compound (VII) is added to the reaction solution, and the reaction is preferably carried out at the same temperature for several minutes to several hours. Examples of the solvent include alcohols such as methanol, ethanol and isopropanol; halogenated hydrocarbons such as chloroform and methylene chloride; hydrocarbons such as benzene, toluene, xylene and cyclohexane; ethers such as ether, dioxane and tetrahydrofuran.

When the compound (V) thus obtained is dehydrated, a carbon-carbon double bond is introduced to obtain a compound (III). Examples of the dehydration method include (a) compound (V)
Examples of the method include sulfonylating the hydroxyl group of (1) and then desulfonic acid, and (b) replacing the hydroxyl group of the compound (V) with a halogen atom and then dehydrohalogenating. As the sulfonylation in the method (a), methanesulfonylation, p-toluenesulfonylation and the like are preferable. For example, to perform methanesulfonylation, a reactive derivative of methanesulfonic acid, such as methanesulfonic acid chloride and compound (V), in a solvent, preferably in the presence of a catalyst,
The reaction is preferably performed at 20 ° C to + 100 ° C for 1 to 50 hours.

As the catalyst, basic catalysts such as pyridine, triethylamine and sodium hydride are preferable. Although the above-mentioned solvent can be used as the solvent, it is also possible to use the above-mentioned catalyst in excess as the solvent. It is industrially advantageous to treat the obtained sulfonyl compound by the conventional method and then to carry out the subsequent desulfonic acid reaction without purification. For the desulfonic acid reaction, a sulfonyl compound and a dehydrating agent are used in a solvent at −20 ° C. to + 100 ° C.
It is preferable to carry out the reaction for 1 to 50 hours. As the dehydrating agent, 1,8-diazabicyclo [5.
4.0] -7-undecene, triethylamine, pyridine and the like. As the solvent, those mentioned above can be used.

As the halogen atom in the method (b), chlorine, bromine, iodine and the like are used, and chlorine is particularly preferable. Examples of the halogenating agent include thionyl halide and phosphorus oxyhalide. In the reaction, compound (V) and a halogenating agent are preferably added in the presence of a catalyst,
It is preferable to carry out in a solvent at −20 ° C. to + 50 ° C. for several minutes to several hours. It is industrially advantageous to treat the resulting halogen compound by a conventional method and then carry out the subsequent dehydrohalogenation reaction without purification. The dehydrohalogenation reaction is preferably carried out by reacting the obtained halogen compound and a dehydrating agent in a solvent at -20 ° C to + 100 ° C for 1 to 50 hours. The above-mentioned can be used as the dehydrating agent and the solvent.

By reacting the compound (III) thus obtained with an acid, the target compound (II) can be obtained. Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as acetic acid and p-toluenesulfonic acid; Lewis acids such as ferric chloride-silica gel; cation exchange resins such as Amberlyst 15. .. It is preferable to carry out the reaction by reacting the reaction compound (III) with an acid in a solvent at −20 ° C. to + 100 ° C. for several minutes to several hours. Besides the above-mentioned solvents, acetone, tetrahydrofuran, etc. can be used as the solvent.

When the compound (II) thus obtained is reacted with the compound (IV) or a salt thereof, the target compound (I) is obtained. This reaction can usually be carried out in a suitable solvent and in the presence of a base, at a temperature of about -10 ° C to the reflux temperature of the solvent, preferably about 5 ° C to about 100 ° C. Examples of the solvent that can be used here include alcohols such as methanol, ethanol and isopropanol; halogenated hydrocarbons such as chloroform and methylene chloride; hydrocarbons such as benzene, toluene, xylene and cyclohexane; ethers, dioxane, tetrahydrofuran and the like. Examples include ether.

Examples of the base that can be used as necessary include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; organic bases such as triethylamine, pyridine and 4-methylaminopyridine. Is mentioned. These bases can be used generally in the range of 0.1 to 100 equivalents, particularly 1 to 10 equivalents per mol of the compound (II). The compound (II), which is the starting material for this reaction, can be used in this reaction without purification after the completion of the previous step. R ₁ or R ₂ in the formula
Alternatively, in the case of producing a compound in which those substituents are the group —A—CH ₂ —C≡C—X, halogenation can be carried out in any of the above steps, but the dehydration step [V → III]
It is particularly preferable that the iodination is carried out at the stage of completing the above.

The target compound can be purified by a usual method, but it may be purified by column chromatography, recrystallization,
A freeze-drying method or the like is preferable. The starting compound (VI) is, for example, alanine converted into ethyl carbamate using ethyl chloroformate, alkylated with methyllithium to give a ketone, and the ketone is protected with a ketal, followed by the method of Moss et al. J. Org. Chem. 31 (1966)
1082] and nitrosated according to the following formula

[Chemical 10] After obtaining a compound represented by the formula (n has the above meaning), potassium t-butyrate is reacted to produce diazotate, and this compound is represented by the general formula CH ₃ —Y (wherein Y is a halogen atom). The compound represented by 1) is reacted.

The compound (I) of the present invention has excellent antifungal activity. For example, candita, cryptococcus,
Fungi infecting warm-blooded animals including humans such as Aspergillus and Trichophyton; Pyricularia, Poritis,
It exhibits excellent antibacterial activity against fungi that are infectious to agricultural and horticultural crops such as Saccharomyces and Septoria and fruit trees.

The minimum inhibitory concentration (μg / m) of the compound (I) of the present invention produced in the examples described below against typical fungi
The measurement results of l) are shown in Tables 1 to 3. The minimum inhibitory concentration was determined by the agar plate dilution method using Sabouraud dextrose medium.

[0019]

[Table 1]

[Table 2]

[Table 3] * C. a. : Candida albicans T. m. : Trichofton Mentaglofites T. r. : Trichofton Rubram

As described above, the compounds of the present invention have excellent antibacterial activity against fungi infecting warm-blooded animals including humans, fungi infecting agricultural and horticultural crops and fruit trees, It is useful as an antifungal agent for medicine, veterinary medicine, and agriculture and horticulture.

When the compound of the present invention is used as an antifungal agent, it can be used by formulating it into a form suitable for each use. For example, when the compound of the present invention is used as a medicine or veterinary medicine (animal drug), an excipient, a binder, a disintegrating agent, a coating agent, an emulsifying agent, a suspending agent, a solvent is added to the compound of the present invention or a salt thereof. , A stabilizer, an absorption aid, an ointment base and the like can be appropriately added, and the drug can be formulated into a dosage form for oral administration, injection administration, rectal administration, external use and the like by a conventional method.

Preparations for oral administration include granules, tablets,
Dragees, capsules, pills, liquids, emulsions, suspensions, etc., such as injection preparations for intravenous injection, intramuscular injection, subcutaneous injection, drip injection, etc., for rectal preparations Examples include suppositories and soft capsules. As an external preparation,
Ointments, lotions, liniments, creams and the like are preferable. In addition, it may be in the form of eye drops, ear drops or the like.

When used as an antifungal agent for agriculture and horticulture,
According to a conventional method, a liquid preparation, an emulsion preparation, a granule preparation, a powder preparation, a dust preparation, a paste preparation and the like can be prepared. When the compound of the present invention is administered to warm-blooded animals including humans, the dose varies over a wide range depending on the type of animal to be administered, the severity of symptoms, body weight, sex, judgment of the doctor to take measures, etc. Usually, about 0.1 to about 500 mg / kg per day
It is the body weight and can be administered once or divided into several times a day. When used for agricultural and horticultural use, the compound of the present invention can be applied to a fungal habitat for soil treatment, foliage treatment, etc., and its application amount is usually about 0.0
05 to about 5 kg / ha.

Reference Example Production of 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane [compound (VI)]: (a) L-alanine 45 g and sodium carbonate 127 g
Is dissolved in 400 ml of water, and ethyl chloroformate 6 is added under ice cooling.
After dropping 4 ml, the mixture was stirred at room temperature for 30 minutes. 35% hydrochloric acid was added to the reaction solution to acidify it, and DIAION HP-
It was adsorbed on 20 columns (6.5 × 60 cm), washed with water and eluted with 70% methanol. The eluate was concentrated under reduced pressure to give N-ethoxycarbonylalanine 6 as an oil.
9 g (yield 96%) was obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 1.26 (3H, t, J = 7 Hz), 1.46 (3H,
d, J = 7 Hz), 4.15 (2H, q, J = 7H)
z), 4.40 (1H, m), 5.28 (1H, br,
d, J = 7 Hz), 7.35 (1H, br.s), IR
Value: νmax, cm ^-1 1719, 1697

(B) 3 g of N-ethoxycarbonylalanine obtained in (a) above was dissolved in 60 ml of tetrahydrofuran under a nitrogen atmosphere, and 3 ml of 48 ml of 1.19N methyllithium ether solution was stirred with vigorous stirring at -78 ° C.
Added in 0 minutes. After stirring for 40 minutes at the same temperature,
The mixture was stirred at room temperature for 1 hour. The reaction solution was poured into cold 10% aqueous phosphoric acid and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and then with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [solvent: chloroform-n-hexane (5: 1) to obtain 1.8 g of 3-ethoxycarbonylamino-2-oxobutane (yield 60%).

¹ H-NMR value: δ CDCl ₃ , ppm 1.24 (3 H, t, J = 7.0 Hz), 1.38 (3
H, d, J = 7.0 Hz), 2.20 (3 H, s),
4.12 (2H, q, J = 7.0Hz), 4.37 (1
H, br. d, J = 7.0 Hz), 4.44 (1H, b
r. s), IR value: νmax, CHCl ₃ , cm ^-1 1706, 1500

(C) Ketone body obtained in (b) above.
34 g and pyridine salt of p-toluenesulfonic acid 500
mg was dissolved in 280 ml of benzene, 22 ml of 1,3-propanediol was added, and the mixture was heated under reflux for 4 hours. The reaction solution was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with benzene. The organic layers were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [solvent: ether-n-hexane (1: 3) to give 3-ethoxycarbonylamino-2,2-propyleneoxybutane 8. 25 g (yield 9
5%) was obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 1.17 (3 H, d, J = 7.0 Hz), 1.24 (3
H, t, J = 7.0 Hz), 1.37 to 1.50 (1
H, m), 1.42 (3H, s), 1.80 to 2.02
(1H, m), 3.76 to 4.06 (5H, m), 4.
11 (2H, q, J = 7.0Hz), 4.90 (1H,
br. s), IR value: νmax, CHCl ₃ , cm ⁻¹ 1701,1507

(D) Compound 4.4 obtained in the above (c)
9 g was dissolved in 30 ml of anhydrous ether under a nitrogen atmosphere,
8.7 g of sodium hydrogen carbonate was added, and the solution was -25
The mixture was cooled to ° C, 9.6 ml of anhydrous ether solution of 3.3 ml of dinitrogen tetraoxide was added dropwise, and the mixture was stirred at the same temperature for 3.5 hours.
The reaction mixture was poured into cold saturated aqueous sodium hydrogen carbonate solution and extracted with cold ether. The ether layer is dried and dried under reduced pressure 30
After concentrating at ℃ or less, water was removed azeotropically. 4.64 g of potassium t-butoxide was added to dimethylformamide 20.
It was suspended in ml and cooled to -30 ° C under a nitrogen atmosphere.
6 ml of the dimethylformamide solution of the N-nitroso compound prepared above was added dropwise thereto, and the mixture was stirred at -30 ° C for 2.5 hours.

Methyl iodide (6.44 ml) was added dropwise to this reaction solution, and the mixture was stirred overnight at room temperature. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was dried and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [solvent: ethyl acetate-n-hexane (1: 3).
The obtained residue was dissolved in 3 ml of pyridine, and acetic anhydride 1.
5 ml was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate, the organic layer was dried over saturated sodium hydrogen carbonate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [solvent: ethyl acetate-n
The product was purified with -hexane (1: 3) to obtain 1.49 g of the desired product (yield 38%).

¹ H-NMR value: δ CDCl ₃ , ppm 1.13 (3 H, d, J = 7.0 Hz), 1.45 (3
H, s), 1.59 to 1.92 (2H, m), 3.85
(4H, m), 4.10 (3H, s), 4.49 (1
H, q, J = 7 Hz), IR value: νmax, CHC
l ₃ , cm ^-1 1503, 1424, 1370, 1330

Example 1 2-Hydroxyimino-3- [2- (4- (3-iodopropargyl) oxyphenyl) -1-propenyl-O
NN-azoxy] -butane [Compound (I): R ₁ = 4-
(3-iodopropargyl) oxyphenyl group, R ₂ =
Methyl group, R ₃ = hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) 249 obtained in Reference Example
mg was dissolved in 3 ml of tetrahydrofuran under a nitrogen atmosphere. Under ice-cooling, 1.15 ml of a cyclohexane solution of 1.7 mmol of lithium diisopropylamide was added and stirred for 30 minutes. To this solution was added a solution of 358 mg of 4-propargyloxyacetophenone in 4 ml of tetrahydrofuran, and the mixture was further stirred under ice cooling for 30 minutes.

Under ice-cooling, 5 ml of 10% aqueous ammonium chloride solution was added to the reaction mixture, the mixture was stirred for 5 minutes, and then extracted with 50 ml of ether. After washing the extract with saturated saline,
It was dried and concentrated under reduced pressure. 650 mg of the obtained oily substance
Silica gel column chromatography (eluent: 50
% (Hexane solution in ether)) and a diastereomeric mixture of 3- [2-hydroxy-2- (4-propargyloxyphenyl) propyl-ONN-azoxy] -2,2-propylenedioxybutane (V) ( 242 mg (yield: 51%) of 1: 1) was obtained as a colorless oil.

Diastereomer (a) ¹ H-NMR value: δ CDCl ₃ , ppm 7.42 (2H, d, J = 9 Hz), 6.95 (2H,
d, J = 9 Hz), 5.24 (1H, br, s), 4.
67 (2H, d, J = 2Hz), 4.51 (1H, d,
J = 12 Hz), 4.39 (1H, d, J = 12H)
z), 4.35 (1H, q, J = 7 Hz), 3.70-
3.97 (4H, m), 2.51 (1H, t, J = 2H
z), 1.71-1.87 (1H, m), 1.54 (3
H, s), 1.46 to 1.59 (1H, m), 1.26
(3H, s), 1.07 (3H, d, J = 7Hz) IR value: νmax, CHCl ₃ , cm ^-1 3430 (br), 3290, 1505, 1225 (b
r)

Diastereomer (b) ¹ H-NMR value: δ CDCl ₃ , ppm 7.40 (2H, d, J = 9 Hz), 6.93 (2H,
d, J = 9 Hz), 5.24 (1H, br, s), 4.
67 (2H, d, J = 2Hz), 4.57 (1H, d,
J = 12 Hz), 4.43 (1H, q, J = 7 Hz),
4.40 (1H, d, J = 12 Hz), 3.77-3.
98 (4H, m), 2.50 (1H, t, J = 2H
z), 1.66 to 1.84 (1H, m), 1.55
1.66 (1H, m), 1.54 (3H, s), 1.3
6 (3H, s), 0.74 (3H, d, J = 7Hz) IR value: νmax, CHCl ₃ , cm ^-1 3420 (br), 3290, 1505, 1225 (b
r)

(2) 155 mg of the hydroxy compound (V) obtained in (1) above was dissolved in 0.4 ml of pyridine,
Under ice-cooling, 0.05 ml of thionyl chloride was added and stirred for 15 minutes. Then 1,8-diazabicyclo [5.4.0]-
0.6 ml of 7-undecene was added, and the mixture was further cooled to 1.5 on ice.
Stir for hours. 50 ml of ether and 5 ml of 1N hydrochloric acid were added to the reaction solution, and the ether layer was separated and washed successively with 5 ml of saturated saline solution, 5 ml of saturated aqueous sodium hydrogencarbonate solution and then 5 ml of saturated saline solution, dried and concentrated under reduced pressure. Concentrated. 170 mg of the obtained oily substance was purified by silica gel column chromatography (solvent: benzene) to give 3- [2- (4-propargyloxyphenyl) -1-.
150 m of propenyl-ONN-azoxy] -2,2-propylenedioxybutane (III ') as colorless oil
g (yield: 71%) was obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 7.33 (2H, d, J = 9 Hz), 7.19 (1H,
q, J = 1 Hz), 6.91 (2H, d, J = 9H
z), 4.66 (1H, q, J = 7Hz), 4.65
(2H, d, J = 2Hz), 3.86 to 3.93 (4
H, m), 2.47 (1H, t, J = 2Hz), 2.3
8 (3H, d, J = 1 Hz), 1.67 to 1.81 (1
H, m), 1.52 to 1.64 (1H, m), 1.43
(3H, s), 1.15 (3H, d, J = 7Hz) IR value: νmax, CHCl ₃ , cm ^-1 3290, 1505, 1225 (br)

(3) 63 mg of the propargy compound (III ') obtained in the above (2) was dissolved in 1.5 ml of methanol, and 0.07 ml of 10M aqueous sodium hydroxide solution was cooled with ice.
And 100 mg of iodine were added, and after the reaction compound became uniform, the mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 50 ml of ether and 5 ml of 1M sodium thiosulfate aqueous solution were added, the ether layer was separated, washed with 5 ml of saturated saline solution, dried and then concentrated under reduced pressure. 83 mg of the obtained oily substance was separated and purified by silica gel preparative thin film chromatography [solvent: ethyl acetate-benzene (1: 5)] to give 3- [2- (4- (3-iodopropargyl) oxyphenyl)-. 1-propenyl-ONN-azoxy]-
85 mg (yield 99%) of 2,2-propylenedioxybutane (III) was obtained as a colorless oily substance.

¹ H-NMR value: δ CDCl ₃ , ppm 7.39 (2H, d, J = 9 Hz), 7.12 (1H,
q, J = 1 Hz), 6.96 (2H, d, J = 9H)
z), 4.85 (2H, s), 4.73 (1H, q, J
= 7 Hz), 3.93 to 3.99 (4H, m), 2.4
5 (3H, d, J = 1 Hz), 1.50 (3H, s),
1.22 (3H, d, J = 7Hz) IR value: νmax, CHCl ₃ , cm ^-1 1505, 1225 (br)

(4) 61 mg of the propylenedioxy compound (III) obtained in (3) above was dissolved in 0.5 ml of acetone, 115 mg of iron chloride-silica gel (11% by weight) was added, and the mixture was stirred at room temperature for 2 hours. .. After adding 10 ml of carbon tetrachloride to the reaction mixture, suction filtration was performed using Celite,
The filtrate was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography [solvent: ether-hexane (1: 1)] to give 3- [2- (4-3-iodopropargyl) oxyphenyl) -1-propenyl-O.
43 mg (yield 79%) of NN-azoxy] -2-oxobutane (II) was obtained as a colorless oily substance.

¹ H-NMR value: δ CDCl ₃ , ppm 7.41 (2H, d, J = 9 Hz), 7.19 (1H,
q, J = 1 Hz), 6.98 (2H, d, J = 9H
z), 4.86 (2H, s), 4.62 (1H, q, J
= 7 Hz), 2.50 (3H, d, J = 1 Hz), 2.
23 (3H, s), 1.51 (3H, d, J = 7Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 1715, 1505, 1220 [α] _D ²³ −21 ° (C 2.9, chloroform). )

(5) 33.2 mg of the oxo compound (II) obtained in (4) above was dissolved in 0.3 ml of methanol,
11.1 mg of hydroxylamine hydrochloride and 0.02 ml of pyridine were added, and the mixture was stirred at room temperature for 10 minutes. 25 ml of ether and 5 ml of water were added to the reaction mixture, and the ether layer was separated, washed with saturated brine, dried and concentrated under reduced pressure. 37 mg of the obtained oily substance was purified by preparative thin-layer chromatography on silica gel [solvent: ethyl acetate-benzene (1: 3)] to obtain colorless anti- and syn-isomers of the oxime hydroxyl group of the target product (I). 11.7 mg (51% yield) as an oil and 9.
2 mg (yield 27%) was obtained.

(A) Anti-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.40 (2H, d, J = 9 Hz), 7.12 (1H,
s), 6.97 (2H, q, J = 9Hz), 4.85
(2H, s), 4.82 (1H, q, J = 7Hz),
2.48 (3H, s), 1.97 (3H, s), 1.4
2 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ^-1 3550, 3270 (br), 1605, 1505, 1
220 (br) [α] _D ²³ + 17 ° (C 2.5, chloroform)

(B) Syn-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.41 (2H, d, J = 9 Hz), 7.16 (1H,
q, J = 1 Hz), 6.97 (2H, d, J = 9H
z), 5.40 (1H, q, J = 7Hz), 4.86
(2H, s), 2.51 (3H, d, J = 1Hz),
1.81 (3H, s), 1.45 (3H, d, J = 7H
z) IR value: νmax, CHCl ₃ , cm ^-1 3560, 3240 (br), 1605, 1505, 1
225 (br) [α] _D ²³ + 84 ° (C 1.0, chloroform)

Example 2 2-Hydroxyimino-3- [2- (2- (3-iodopropargyl) oxyphenyl) -1-propenyl-O
NN-azoxy] -butane [Compound (I): R ₁ = 2-
(3-iodopropargyl) oxyphenyl group, R ₂ =
Methyl group, R ₃ = hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) and 2 obtained in Reference Example
Example 1 using propargyloxyacetophenone
Reaction treatment is carried out in the same manner as in (1), and 3- [2-hydroxy-
2- (2-propargyloxyphenyl) -propyl-
A mixture of diastereomers of ONN-azoxy] -2,2-propylenedioxybutane (V) (1: 1) was obtained.

Diastereomer (a) (colorless oil) ¹ H-NMR value: δ CDCl ₃ , ppm 7.70 (1 H, dd, J = 8, 2 Hz), 7.23
(1H, td, J = 8, 2Hz), 6.99 (1H,
t, J = 8 Hz), 6.94 (1H, d, J = 8H)
z), 5.39 (1H, s), 5.15 (1H, d, J
= 12 Hz), 4.75 (2H, d, J = 2 Hz),
4.45 (1H, d, J = 12Hz), 4.41 (1
H, q, J = 7 Hz), 3.77 to 3.88 (2H,
m), 3.48 to 3.57 (1H, m), 3.32 to
3.42 (1H, m), 2.54 (1H, t, J = 2H
z), 1.59 to 1.70 (2H, m), 1.61 (3
H, s), 1.23 (3H, s), 0.96 (3H,
d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ^-1 3430 (br), 3290, 1485, 1225 (b
r)

Diastereomer (b) Colorless prismatic crystals (mp 127.0-130.5)
C) ¹ H-NMR value: δ CDCl ₃ , ppm 7.66 (1 H, dd, J = 8, 2 Hz), 7.24
(1H, td, J = 8, 2Hz), 6.98 (1H,
t, J = 8 Hz), 6.94 (1H, d, J = 8H)
z), 5.28 (1H, s), 5.23 (1H, d, J
= 11 Hz), 4.73 (2H, d, J = 2 Hz),
4.35 (1H, d, J = 11Hz), 4.36 (1
H, q, J = 7 Hz), 3.74 to 3.91 (4H,
m), 2.54 (1H, t, J = 2Hz), 1.58-
1.72 (2H, m, Hm), 1.63 (3H, s),
1.33 (3H, s), 0.44 (3H, d, J = 7H
z) IR value: νmax, CHCl ₃ , cm ^-1 3440 (br), 3270, 1485, 1385, 1
240, 1090

(2) Using the hydroxy compound (V) obtained in (1) above, the reaction and treatment were carried out in the same manner as in Example 1 (2) to give 3- [2- (2-propargyloxyphenyl)].
-1-Propenyl-ONN-azoxy) -2,2-propylenedioxybutane (III ') was obtained as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.32 (1H, ddd, J = 8, 7, 2 Hz), 7.
21 (1H, dd, J = 7, 2 Hz), 7.04 (1
H, d, J = 8Hz, 6.99 (1H, t, J = 7H
z), 6.94 (1H, q, J = 1 Hz), 4.74
(1H, q, J = 7Hz), 4.73 (2H, d, J =
2Hz), 3.93 to 3.99 (4H, m), 2.25
(1H, t, J = 2Hz), 2.43 (3H, d, J =
1 Hz), 1.60 to 1.87 (2H, m), 1.50
(3H, s), 1.22 (3H, d, J = 7Hz) IR value: νmax, CHCl ₃ , cm ^-1 3290, 1485, 1450

(3) 3- (2- (2- (3-iodopropargyl) )
Oxyphenyl) -1-propenyl-ONN-azoxy] -2,2-propylenedioxybutane (III) was obtained as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.33 (1H, t, J = 7 Hz), 7.21 (1H,
d, J = 7 Hz), 7.03 (1H, d, J = 7H
z), 6.99 (1H, t, J = 7Hz), 6.94
(1H, s), 4.86 (2H, s), 4.74 (1
H, q, J = 7 Hz), 3.93 to 3.99 (4H,
m), 2.42 (3H, s), 1.60 to 1.88 (2
H, m), 1.50 (3H, s), 1.22 (3H,
d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 1485, 1450

(4) Using the propylenedioxy compound (III) obtained in (3) above, the reaction and treatment were carried out in the same manner as in Example 1 (4) to give 3- [2- (2- (3- Iodopropargyl) oxyphenyl) -1-propenyl-ONN-azoxy] -2-oxobutane (II) was obtained as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.35 (1 H, ddd, J = 8, 7, 2 Hz), 7.
21 (1H, dd, J = 7, 2 Hz), 7.04 (1
H, d, J = 8 Hz, 7.01 (1H, t, J = 7H
z), 7.01 (1H, q, J = 1 Hz), 4.87
(2H, s), 4.61 (1H, q, J = 7Hz),
2.45 (3H, d, J = 1 Hz), 2.23 (3H,
s), 1.50 (3 H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 1715, 1485, 1450 [α] _D ²³ −37 ° (C 3.5, chloroform).

(5) Using the oxo compound (II) obtained in (4) above, the reaction and treatment were carried out in the same manner as in Example 1 (5) to obtain the anti- and syn-oxy groups related to the oxime hydroxyl group of the desired product (I). -Each isomer was obtained as a colorless oil.

Anti-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.33 (1 H, ddd, J = 8, 7, 2 Hz), 7.
20 (1H, dd, J = 7, 2Hz), 7.03 (1
H, d, J = 8 Hz), 7.00 (1H, t, J = 7H
z), 6.94 (1H, q, J = 1 Hz), 4.86
(2H, s), 4.83 (1H, q, J = 7Hz),
2.43 (3H, d, J = 1 Hz), 1.98 (3H,
s), 1.41 (3 H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3550, 3260 (br), 1485, 1445 [α] _D ²³ + 8.0 ° (C 0.56) , Chloroform)

Syn-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.34 (1 H, ddd, J = 8, 7, 2 Hz), 7.
21 (1H, dd, J = 7, 2 Hz), 7.04 (1
H, d, J = 8 Hz, 7.01 (1H, t, J = 7H
z), 6.97 (1H, q, J = 1 Hz), 5.42
(1H, q, J = 7Hz), 4.87 (2H, s),
2.46 (3H, d, J = 1 Hz), 1.83 (3H,
s), 1.48 (3 H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 3560, 3240 (br), 1485, 1450 [α] _D ²³ + 36 ° (C 0.25, chloroform) )

Example 3 2-Hydroxyimino-3- [2- (3- (3-iodopropargyl) oxyphenyl) -1-propenyl-O
NN-azoxy] -butane [Compound (I): R ₁ = 3-
(3-iodopropargyl) oxyphenyl group, R ₂ =
Methyl group, R ₃ = hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) and 3 obtained in Reference Example
Example 1 using propargyloxyacetophenone
Reaction and treatment are carried out in the same manner as in (1) to give 3- [2-hydroxy-2- (3-propargyloxyphenyl) propyl-
A mixture of diastereomers of ONN-azoxy] -2,2-propylenedioxybutane (V) (1: 1) was obtained as an oil.

Diastereomer (a) ¹ H-NMR value: δ CDCl ₃ , ppm 7.26 (1 H, t, J = 8 Hz), 7.16 (1 H,
br, s), 7.08 (1H, d, J = 8 Hz), 6.
87 (1H, dd, J = 8, 3Hz), 5.28 (1
H, br, s), 4.69 (2H, d, J = 2Hz),
4.54 (1H, d, J = 13Hz), 4.41 (1
H, d, J = 13 Hz), 4.36 (1H, q, J = 7)
Hz), 3.69 to 3.97 (4H, m), 2.52
(1H, t, J = 2Hz), 1.71-1.86 (1
H, m), 1.55 (3H, s), 1.48 to 1.59
(1H, m), 1.26 (3H, s), 1.06 (3
H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ^-1 3430 (br), 3290, 1600, 1500, 1
230 (br)

Diastereomer (b) ¹ H-NMR value: δ CDCl ₃ , ppm 7.25 (1H, t, J = 8 Hz), 7.14 (1H,
t, J = 2 Hz), 7.06 (1H, br, d, J = 8)
Hz), 6.87 (1H, dd, J = 8, 2Hz),
5.29 (1H, br, s), 4.69 (2H, d, J
= 2 Hz), 4.59 (1H, d, J = 12 Hz),
4.42 (1H, d, J = 12Hz), 4.42 (1
H, q, J = 7 Hz), 3.77 to 3.96 (4H,
m), 2.52 (1H, t, J = 2Hz), 1.68 ~
1.82 (1H, m), 1.58 to 1.66 (1H,
m), 1.55 (3H, s), 1.36 (3H, s),
0.74 (3H, d, J = 7Hz) IR value: νmax, CHCl ₃ , cm ^-1 3420 (br), 3290, 1600, 1500, 1
225 (br)

(2) Using the hydroxy compound (V) obtained in (1) above, reacting and treating in the same manner as in Example 1 (2) to give 3- [2- (3-propargyloxyphenyl)].
-1-Propenyl-ONN-azoxy) -2,2-propylenedioxybutane (III ') was obtained as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.31 (1H, t, J = 8 Hz), 7.12 (1H,
q, J = 1 Hz), 7.06 (1H, br.d, J = 8
Hz), 7.03 (1H, t, J = 2Hz), 6.98
(1H, dd, J = 8, 2Hz), 4.72 (1H,
d, J = 2 Hz) 4.72 (1H, q, J = 7 Hz),
3.93 to 4.00 (4H, m), 2.52 (1H,
t, J = 2 Hz), 2.45 (3H, d, J = 1H)
z), 1.74-1.89 (1H, m), 1.60
1.71 (1H, m), 1.51 (3H, s), 1.2
2 (3H, d, J = 7Hz) IR value: νmax, CHCl ₃ , cm ^-1 3290, 1570, 1480, 1220 (br)

(3) Using the propargy compound (III ') obtained in (2) above, a reaction was carried out in the same manner as in Example 1 (3),
This was treated to give 3- [2- (3- (3-iodopropargyl) oxyphenyl) -1-propenyl-ONN-azoxy] -2,2-propylenedioxybutane (III) as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.31 (1H, t, J = 8 Hz), 7.12 (1H,
q, J = 1 Hz), 7.07 (1H, br.d, J = 8)
Hz), 7.01 (1H, t, J = 2 Hz), 6.96
(1H, dd, J = 8, 2Hz), 4.85 (2H,
s), 4.73 (1H, q, J = 7Hz), 3.93-
3.99 (4H, m), 2.45 (3H, d, J = 1H
z), 1.74-1.89 (1H, m), 1.61-
1.71 (1H, m), 1.51 (3H, s), 1.2
2 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 1575, 1480, 1215 (br)

(4) Using the propylenedioxy compound (III) obtained in (3) above, the reaction and treatment were carried out in the same manner as in Example 1 (4) to give 3- [2- (3- (3- Iodopropargyl) oxyphenyl) -1-propenyl-ONN-azoxy] -2-oxobutane (II) was obtained as an oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.33 (1 H, t, J = 8 Hz), 7.18 (1 H,
q, J = 1 Hz), 7.08 (1H, br.d, J = 8
Hz), 7.02 (1H, t, J = 2Hz), 6.99
(1H, dd, J = 8, 2Hz), 4.85 (2H,
s), 4.62 (1H, q, J = 7Hz), 2.50
(3H, d, J = 1 Hz), 2.24 (3H, s),
1.52 (3 H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ⁻¹ 1715, 1595, 1440 (br), 1285 [α] _D ²³ −30 ° (C 1.7, chloroform)

(5) Using the oxo compound (II) obtained in (4) above, the reaction and treatment were carried out in the same manner as in Example 1 (5) to obtain the anti- and syn-compounds relating to the oxime hydroxyl group of the desired product (I). -Each isomer was obtained as a colorless oil.

Anti-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.32 (1 H, t, J = 8 Hz), 7.12 (1 H,
br. s), 7.06 (1H, d, J = 8 Hz), 7.
01 (1H, br.s), 6.97 (1H, d, J = 8)
Hz), 4.85 (2H, s), 4.83 (1H, q,
J = 7 Hz), 2.47 (3H, s), 1.98 (2
H, s), 1.42 (3H, d, J = 7 Hz) IR value: νmax, CHCl ₃ , cm ^-1 3550, 3270 (br), 1695, 1465, 1
285 [α] _D ²³ + 7.1 ° (C 0.68, chloroform)

Syn-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.33 (1H, t, J = 8 Hz), 7.16 (1H,
q, J = 1 Hz), 7.08 (1H, br.d, J = 8
Hz), 7.02 (1H, t, J = 2 Hz), 6.98
(1H, dd, J = 8, 2Hz), 5.41 (1H,
q, J = 7 Hz), 4.86 (2H, s), 2.51
(3H, d, J = 1 Hz), 1.83 (3H, s),
1.46 (3H, d, J = 7Hz) IR value: νmax, CHCl ₃ , cm ^-1 3560, 3240 (br), 1600, 1460, 1
285 [α] _D ²³ + 67 ° (C 0.19, chloroform)

Example 4 2-Hydroxyimino-3- [4 '-(3-iodopropargyl) oxystyryl-ONN-azoxy] -butane [Compound (I): R ₁ = 4- (3-iodopropargyl) oxyphenyl] Group, R ₂ = R ₃ = hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) 743 obtained in Reference Example
mg and 4-propargyloxybenzaldehyde (V
I) Using 1.08 g, the same reaction as in Example 1 (1),
Treated to give 3- [2-hydroxy-2- (4-propargyloxyphenyl) -ethyl-ONN-azoxy]-
Mixture of diastereomers of 2,2-propylenedioxybutane (V) (4: 5) as a colorless oil 1.00
g (yield 73%) was obtained.

Diastereomer (a) ¹ H-NMR value: δ CDCl ₃ , ppm 7.35 (2H, d, J = 9 Hz), 6.99 (2H,
d, J = 9 Hz), 5.32 (1H, br.d, J = 8)
Hz), 4.70 (2H, d, J = 2Hz), 4.54
(1H, dd, J = 13, 2Hz), 4.36 (1H,
dd, J = 13,8 Hz), 4.32 (1H, br,
s), 3.91 to 4.06 (2H, m), 3.86 (1
H, q, J = 7 Hz), 3.74 to 3.86 (2H,
m), 2.52 (1H, t, J = 2Hz), 1.87-
2.06 (1H, m), 1.47 (3H, s), 1.3
4 to 1.44 (1H, m), 1.19 (3H, d, J =
7 Hz) IR value: νmax, CHCl ₃ , cm ^-1 3410 (br), 3240, 1495, 1220 (b
r), 1155

Diastereomer (b) ¹ H-NMR value: δ CDCl ₃ , ppm 7.36 (2H, d, J = 9 Hz), 6.98 (2H,
d, J = 9 Hz), 5.32 (1H, br, d, J = 9)
Hz), 4.69 (2H, d, J = 2Hz), 4.51
(1H, dd, J = 13,9Hz), 4.48 (1H,
br, s), 4.27 (1H, dd, J = 13, 2H
z), 3.92 to 4.06 (2H, m), 3.96 (1
H, q, J = 6 Hz), 3.77 to 3.87 (2H,
m), 2.51 (1H, t, J = 2Hz), 1.89-
2.07 (1H, m), 1.50 (3H, s), 1.3
3 to 1.45 (1H, s), 1.20 (3H, d, J =
6 Hz) IR value: νmax, CHCl ₃ , cm ^-1 3390 (br), 3300, 1495, 1220 (b
r), 1155

(2) Using 449 mg of the hydroxy compound (V ') obtained in (1) above, the reaction and treatment were carried out in the same manner as in Example 1 (2) to give 3- (4'-propargyloxystyryl-ONN. -Azoxy) -2,2-propylenedioxybutane (III ') as a colorless oil 239 mg
(Yield 56%) was obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 7.76 (1 H, d, J = 14 Hz), 7.57 (1
H, d, J = 14 Hz), 7.45 (2H, d, J = 9)
Hz), 6.99 (2H, d, J = 9Hz), 4.73
(2H, d, J = 2Hz), 4.71 (1H, q, J =
7 Hz), 3.92 to 4.02 (4H, m), 2.55
(1H, t, J = 2Hz), 1.77 to 1.92 (1
H, m), 1.61 to 1.69 (1H, m), 1.51
(3H, s), 1.22 (3H, d, J = 7Hz) IR
Value: νmax, CHCl ₃ , cm ^-1 3290, 1605, 1510, 1450, 1230
(Br)

(3) Using 229 mg of the propargy compound (III ') obtained in (2) above, the reaction and treatment were carried out in the same manner as in Example 1 (3) to give 3- [4'-(3-iodopropargyl). ) Oxystyryl-ONN-azoxy] -2,2
277 mg (yield 88%) of propylenedioxybutane (III) was obtained as a colorless oil.

¹ H-NMR value: δ CDCl ₃ , ppm 7.76 (1 H, d, J = 14 Hz), 7.57 (1
H, d, J = 14 Hz), 7.45 (2H, d, J = 9)
Hz), 6.97 (2H, d, J = 9 Hz), 4.86
(2H, s), 4.71 (1H, q, J = 6Hz),
3.90 to 4.01 (4H, m), 1.77 to 1.92
(1H, m), 1.57 to 1.68 (1H, m), 1.
51 (3H, s), 1.22 (3H, d, J = 6Hz) IR value: νmax, CHCl ₃ , cm ^-1 1605, 1505, 1450, 1225 (br)

(4) Using 249 mg of the propylenedioxy compound (III) obtained in (3) above, Example 1 (4)
Is reacted and treated in the same manner as in 3- [4 '-(3-iodopropargyl) oxystyryl-ONN-azoxy] -2.
-225 mg of a crude oil of oxobutane (II) was obtained. Recrystallization of this crude oil from methanol gave a melting point of 86 ° C.
Fine yellow needle crystals of (decomposition) were obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 7.79 (1 H, d, J = 14 Hz), 7.58 (1
H, d, J = 14 Hz), 7.47 (2H, d, J = 9)
Hz), 6.99 (2H, d, J = 9Hz), 4.87
(2H, s), 4.68 (1H, q, J = 7Hz),
2.21 (3H, s), 1.51 (3H, d, J = 7H
z) IR value: νmax, CHCl ₃ , cm ⁻¹ 1715, 1600, 1510, 1375, 1300,
1250, 1170

(5) Using 225 mg of the crude oil of oxo compound (II) obtained in (4) above, the reaction and treatment were carried out in the same manner as in Example 1 (5) to obtain the oxime hydroxyl group of the desired product (I). The anti- and syn-isomers of were obtained as colorless oils, 136 mg and 52 mg, respectively.

Anti-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.77 (1 H, d, J = 14 Hz), 7.52 (1
H, d, J = 14 Hz), 7.46 (2H, d, J = 9)
Hz), 6.98 (2H, d, J = 9 Hz), 4.87
(1H, q, J = 7Hz), 4.86 (2H, s),
1.98 (3H, s1.42 (3H, d, J = 7Hz) IR value: νmax, CHCl ₃ , cm ^-1 3550, 3260 (br), 1605, 1505, 1
455, 1220 (br), 1170 [α] _D ²³ + 21 ° (C 1.2, chloroform)

Syn-isomer ¹ H-NMR value: δ CDCl ₃ , ppm 7.79 (1 H, d, J = 14 Hz), 7.53 (1
H, d, J = 14 Hz), 7.47 (2H, d, J = 9)
Hz), 6.98 (2H, d, J = 9 Hz), 5.43
(1H, q, J = 7Hz), 4.87 (2H, s),
1.79 (3H, s1.46 (3H, d, J = 7Hz) IR value: νmax, CHCl ₃ , cm ^-1 3550, 3260 (br), 1605, 1505, 1
455, 1220 (br), 1170 [α] _D ²³ + 44 ° (C 0.63, chloroform)

Example 5 3- (2'-chlorostyryl-ONN-azoxy) -2
-Hydroxyimino-butane [Compound (I): R ₁ = 2
-Chlorophenyl group, R ₂ = R ₃ = hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (V) 297 obtained in Reference Example
mg and O-chlorobenzaldehyde (VII) 0.36
Using ml, the reaction and treatment were carried out in the same manner as in Example 1 (1),
3- [2-chlorophenyl) -2-hydroxyethyl-
ONN-azoxy] -2,2-propylenedioxybutane (V) (463 mg, yield 84%) was obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 1.06 (3 H, d, J = 6.34 Hz), 1.28
(3H, d, J = 6.59 Hz), 1.46 (3H,
s), 1.48 (1H, s), 1.92 to 2.05 (4
H), 3.76 to 4.90 (16H), 5.62 to 5.
68 (2H), 7.24 to 7.77 (8H)

(2) 3- (2-chlorostyryl-ONN-
Azoxy) -2,2-propylenedioxybutane (III
) Was obtained (222 mg, yield 82.3%).

¹ H-NMR value: δ CDCl ₃ , ppm 1.23 (3H, d, J = 6.35 Hz), 1.51
(3H, s), 1.62 to 1.87 (2H), 3.94
˜4.01 (4H), 4.71 (1H, q, J = 6.3
5 Hz), 7.25 to 7.56 (4H), 7.94 (2
H, q, J = 13.67 Hz) IR value: νmax, CHCl ₃ , cm ^-1 1460 UV (EtOH, λmax) [nm] 276 [α] _D ²³ + 34.4 ° (C 1.0, CHCl ₃ ).

(3) Using 1 mg of the propylenedioxy compound (III) obtained in (2) above, Example 1 (4)
Reaction and treatment were carried out in the same manner as above to obtain a crude oily substance. This crude oily substance was reacted and treated in the same manner as in Example 1 (5) without purification to give the target compound (I) as a mixture (3: 1) of anti- and syn-isomers (18.3 mg, yield). Rate 66.2
%)Obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 1.43 (3H, d, J = 6.84 Hz), 1.47
(3H, d, J = 7.33Hz), 1.82 (3H,
s), 1.99 (3H, s), 4.88 (1H, q, J
= 6.84 Hz), 7.29 to 7.63 (10H,
s), 8.18 to 8.23 (2H, s) IR value: νmax, CHCl ₃ , cm ^-1 1458.

Example 6 3- [2- (2-chlorophenyl) -1-propenyl-
ONN-azoxy] -2-hydroxyimino-butane [Compound (I): R ₁ = 2-chlorophenyl group, R ₂ =
R ₃ = hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) 320 obtained in Reference Example
mg and O-chloroacetophenone 0.45 ml, reacted and treated in the same manner as in Example 1 (1) to give 3- [2
-Chlorophenyl) -2-hydroxypropyl-ONN
194 mg (yield 33%) of -azoxy] -2,2-propylenedioxybutane (V) was obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 0.46 (3 H, d, J = 6.35 Hz), 1.01
(3H, d, J = 6.35Hz), 1.17 (3H,
s), 1.36 (3H, s), 1.71 (3H, s),
1.72 (3H, s), 1.45 to 1.80 (4H),
3.65 to 3.85 (8H), 4.25 (1H, q, J
= 6.35 Hz), 4.34 (1H, q, J = 6.35)
Hz), 4.42 (1H, d, J = 12.21 Hz),
4.53 (1H, d, J = 12.7Hz), 5.31
(1H, d, J = 12.7 Hz), 5.43 (1H,
d, J = 12.2 Hz), 5.52 (1H, s), 5.
66 (1H, s), 7.19 to 7.22 (6H), 7.
84 to 7.90 (2H)

(2) 3- [2- (2-chlorophenyl)-
34.9 mg of 1-propenyl-ONN-azoxy) -2,2-propylenedioxybutane (III) (yield 20
%)Obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 1.22 (3H, d, J = 6.35 Hz), 1.50
(3H, s), 2.45 (3H, d, J = 1.95H
z), 3.93 to 3.99 (4H), 4.71 (1H,
q, J = 6.35 Hz), 6.88 (1H, d, J =
1.95 Hz), 7.24 to 7.42 (4H) IR value: νmax, CHCl ₃ , cm ^-1 1470 UV (EtOH, λmax) [nm] 233 [α] _D ²³ + 26.4 ° (C 1. 0, CHCl ₃ )

(3) Example 1 was prepared using 27.4 mg of the propylenedioxy compound (III) obtained in (2) above.
Reaction and treatment were carried out in the same manner as in (4) to obtain a crude oily product (II). This crude oil was purified without purification of Example 1
By reacting and treating in the same manner as in (5), the target product (I) was prepared as a mixture of anti- and syn-isomers (4: 1) at 18.5.
mg (yield 77.8%) was obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 1.42 (3H, d, J = 6.35 Hz), 1.44
(3H, d, J = 6.70 Hz), 1.83 (3H,
s), 1.98 (3H, s), 2.45 (3H, d, J
= 1.95 Hz), 2.48 (3H, d, J = 1.95)
Hz), 4.83 (1H, q, J = 6.35Hz),
5.43 (1H, q, J = 6.70 Hz), 6.88
(1H, d, J = 1.95Hz), 6.90 (1H,
d, J = 1.95 Hz), 7.25 to 7.43 (8H) IR value: νmax, CHCl ₃ , cm ⁻¹ 1463

Example 7 3- [2- (2,4-difluorophenyl) -1-propenyl-ONN-azoxy] -2-hydroxyiminobutane [Compound (I): R ₁ = 2-fluorophenyl group,
Production of R ₂ = methyl group, R ₃ = 4-fluoro]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (V) 309 obtained in Reference Example
mg and 2,4-difluoroacetophenone 0.5 ml
Was treated and treated in the same manner as in Example 1 (1) to give 3-
[2- (2,4-Difluorophenyl) -2-hydroxypropyl-ONN-azoxy] -2,2-propylenedioxybutane (V) 419.4 mg (yield 74.2)
%)Obtained.

(2) Using 419 mg of the hydroxy compound (V) obtained in (1) above, the reaction and treatment were carried out in the same manner as in Example 1 (2) to give 3- [2- (2,4-difluorophenyl). ) -1-Propenyl-ONN-azoxy] -2,2
-Propylenedioxybutane (III) 65.4 mg
(Yield 16.5%) was obtained.

(3) Using 1 mg of the propylenedioxy compound (III) obtained in (2) above, Example 1 (4)
The reaction and treatment were carried out in the same manner as in (5) and (5) to obtain 38.8 mg (yield 68.8%) of the target product (I) as a mixture (2: 1) of anti-isomer and syn-isomer. ¹ H-NMR value: δ CDCl ₃ , ppm 1.42 (3H, d, J = 6.84 Hz), 1.45.
(3H, d, J = 6.84Hz), 1.83 (3H,
s), 1.98 (3H, s), 2.44 (3H, d, J
= 1.95 Hz), 2.47 (3H, d, J = 1.95)
Hz), 4.83 (1H, q, J = 6.84Hz),
5.41 (1H, q, J = 6.84Hz), 6.87
(1H, d, J = 1.95 Hz), 6.84 to 7.30
(6H, s) IR value: νmax, CHCl ₃ , cm ^-1 1464

Example 8 3- (1-Hexenyl-ONN-azoxy) -2- (3
-Iodopropargyloxyimino) -butane [Compound (1): R ₁ = n-butyl group, R ₂ = hydrogen atom, R ₃ =
3-iodopropargyl group]: (1) 0.536 ml of diisopropylamine and 1.59
3- (methyl-ONN-azoxy) -obtained in Reference Example was added to 2.39 ml of N-butyllithium hexane solution of N to 10 ml of a tetrahydrofuran solution of lithium diisopropylamide prepared under ice cooling under a nitrogen atmosphere.
2.4 ml of tetrahydrofuran containing 549 mg of 2,2-propylenedioxybutane (VI) was added dropwise. 0.953 ml of n-valeraldehyde (VII) was added to this solution, and the mixture was further stirred for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [solvent: ethyl acetate-n-hexane (1: 3)] to give 3- (2-hydroxyhexyl-ONN-azoxy) -2,2-propylenedioxybutane (V). 436 mg (yield: 54%) was obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 0.90 (3 H, br.t, J = 8.0 Hz), 1.1
6, 1.18 (total 3H, each d, J = 7.0Hz), 1.
24-1.94 (6H, m), 1.47 (3H, s),
3.66 (1H, br.s), 3.84 to 3.98 (4
H, m), 4.0 to 4.37 (3H, m), 4.60
(1H, m) IR value: νmax, CHCl ₃ , cm ^-1 1497, 1370

(2) 160 mg of the hydroxy compound (V) obtained in (1) above was dissolved in 1.5 ml of pyridine,
Add 0.058 ml of methanesulfonyl chloride under ice cooling,
Stir overnight at room temperature. The reaction solution was cooled to 0 ° C., one drop of water was added, and the mixture was stirred at room temperature for 30 minutes. Further, 10 ml of water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution, and then dried,
Crude methanesulfonyl compound 220 concentrated under reduced pressure
mg was obtained. This methanesulfonyl compound was added to toluene 2
It was dissolved in 1 ml of 1,8-diazabicyclo [5.
4.0] -7-Undecene (0.14 ml) was added, and the mixture was stirred at room temperature overnight. 10 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution, dried and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [solvent: ether-n-hexane (1: 5)],
3- (1-hexenyl-ONN-azoxy) -2,2-
133 mg of propylenedioxybutane (III) (yield 89
%) Was obtained.

¹ H-NMR value: δ CDCl ₃ , ppm 0.90 (3 H, t, J = 7.0 Hz), 1.18 (3
H, d, J = 7.0 Hz), 1.22 to 1.53 (4
H, m), 1.46 (3H, s), 1.56 to 1.68
(1H, m), 1.72-1.90 (1H, m), 2.
12 to 2.26 (2H, m), 3.86 to 4.02 (4
H, m), 4.64 (1H, q, J = 7.0 Hz),
6.98 (2H, m) IR value: νmax, CHCl ₃ , cm ^-1 1405, 1380, 1316, 964

(3) 80 mg of the propylenedioxy compound (III) obtained in (2) above was dissolved in 3 ml of acetone, 40 mg of ferric chloride-silica gel was added, and the mixture was stirred at room temperature for 1 hour.
Stir for hours. The reaction mixture was filtered through Celite, 10 ml of water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [solvent: ether-n-hexane (1: 5)],
31 mg (yield 50%) of 3- (1-hexenyl-ONN-azoxy) -2-oxobutane [(II): KA-767A] was obtained.

Specific rotation: [α] _D ²² −160 ° (c
1.0, CHCl ₃ ) ¹ H-NMR value: δ CDCl ₃ , ppm 0.89 (3H, t, J = 7.0 Hz), 1.27 to.
1.48 (4H, m), 1.37 (3H, d, J = 7.
5Hz), 1.22 to 1.53 (4H, m), 2.10
(3H, s), 2.22 (2H, brq, J = 7.5H
z), 4.52 (1H, q, J = 7.5 Hz), 6.9.
0 (1H, dt, J = 14.0Hz, 7.5Hz),
7.23 (1H, dd, J = 14.0Hz, 1.0H
z) IR value: νmax, CHCl ₃ , cm ⁻¹ 1717, 1463

(4) 50 mg of N- (3-iodopropargyloxy) phthalimide (IV ') was added to 0.8 of ethanol.
Dissolve in ml, add 7.7 mg of hydrazine monohydrate,
The mixture was stirred at 0 ° C for 40 minutes. After the reaction, the resulting insoluble matter was filtered off, and the oxo compound (II) 2 obtained in (3) above was added to the filtrate.
8.5 mg was added, and the mixture was stirred at room temperature for 4 hours. After the reaction, the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated potassium hydrogen sulfate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate-hexane) to obtain 39.2 mg of a mixture of anti-isomer and syn-isomer of the target product (I). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.36 (3H, d, 4-CH ₃ ), 1.92 (3H,
_{s, 1-CH 3),} 4.79 (2H, s, OCH 2),
4.80 (1H, q, 3-CH-), 6.95 (2H,
s, olefinic H)

Example 9 3- (Styryl-ONN-azoxy) -2-hydroxyimino-butane [Compound (I): R ₁ = phenyl group, R
₂ = R ₃ = hydrogen atom]: (1) 481 mg of the compound (VI) obtained in Reference Example was dissolved in 14 ml of tetrahydrofuran and cooled to −35 ° C., and then 2.2 ml of lithium diisopropylamide (1.5
M hexane solution) was added and stirred for 30 minutes. Then
0.52 ml of benzaldehyde was added, and the mixture was further stirred for 40 minutes. After the reaction, saturated ammonium chloride solution 14m
1 was added and the reaction solution was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 3- (2-hydroxy-2-phenylethyl-ONN-azoxy) -2,2.
-476.5 mg (yield 63.3%) of a mixture of diastereomers of propylenedioxybutane (V) was obtained.

¹ H-NMR value: δ CDCl ₃ , TM
S, ppm 1.18,1.22 (3H, d , 4-CH 3), 1.4
8,1.52 (3H, s, 1- CH 3), 1.98 (2
H, m), 3.91 (4H, m), 4.44 (3H,
m), 5.38 (1H, m), 7.40 (5H, m, aromatic nucleus H)

(2) 476.5 mg of the hydroxy compound (V) obtained in (1) above was dissolved in 11 ml of toluene, and 1,8-diazabicyclo [5.4.0] -under ice cooling.
0.73 ml of 7-undecene and 0.25 ml of methanesulfonyl chloride were sequentially added dropwise. After the dropping, the mixture was stirred at room temperature for 4 hours, reacted, diluted with water-ethyl acetate, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated potassium hydrogensulfate solution, water, saturated sodium hydrogencarbonate solution, water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate-
Hexane) to give 3- (styryl-ONN-azoxy) -2,2, -propylenedioxybutane (III) 3.
44 mg (yield 76.9%) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.23 (3H, d, 4-CH ₃ ), 1.51 (3H,
_{s, 1-CH 3),} 1.73 (2H, m), 3.97
(4H, m), 4.71 (1H, q, 3-CH-),
7.45 (5H, m, aromatic nucleus H), 7.73 (2H, a
bq, olefinic H)

(3) Propylene di obtained in (2) above
Dissolve 30 mg of oxy compound (III) in 2 ml of acetone
Then, add 60 mg of ferric chloride-silica gel and at room temperature.
Stir for 1 hour. After the reaction, remove silica gel and remove diethyl ether.
Dilute with ether and wash the ether layer with water and saturated saline.
Then, the extract is dried over sodium sulfate and concentrated under reduced pressure. The residue is meta
Dissolve in 1 ml of knoll, hydroxylamine hydrochloride 1
1.5 mg (1.5 equivalents) and 0.05 ml of pyridine were added.
Then, stir for 30 minutes at room temperature. After the reaction, remove the solvent under reduced pressure
Concentrate with and purify by silica gel thin-layer chromatography.
To obtain the anti-isomer and syn-isomer of the target compound (I).
20 mg of a mixture was obtained.¹ H-NMR value: δ CDCl₃, TMS, ppm 1.42, 1.46 (3H, d, 4-CH₃) 1.8
1,1.99 (3H, s, 1-CH₃), 4.88,
5.46 (1H, q, 3-CH-), 7.37 to 7.5
8 (5H, m, aromatic nucleus H), 7.60, 7.02 (1
H, d, 1 '= CH-), 7.83 (1H, d, 2'-
CH =), 8.10 (1H, brs, OH) ¹ H-NMR value: δ CDCl₃, TMS, ppm (
Anti-isomer 1.42 (3H, d, 4-CH)₃), 1.96 (3H,
s, 1-CH₃), 4.80 (2H, s, -CH
₂-), 4.87 (1H, q, -CH-), 7.45
(5H, m, aromatic nucleus H), 7.69 (2H, abq, oh
Refining H), syn-isomer 1.44 (3H, d, 4-CH₃), 1.83 (3H,
s, 1-CH₃), 4.79 (2H, s, -CH
₂-), 5.35 (1H, q, -CH-), 7.45
(5H, m, aromatic nucleus H), 7.69 (2H, abq, oh
Refinability H)

Example 10 3- (2'-chlorostyryl-ONN-azoxy) -2
-(3-Iodopropargyloxyimino) -butane [Compound (I): R ₁ = 2-chlorophenyl group, R ₂ =
Production of hydrogen atom, R ₃ = 3-iodopropargyl group]:
3- (2'-chlorostyryl-ON obtained in Example 5
N-azoxy) -2-hydroxyimino-butane (I)
74.3 mg was dissolved in dimethylformamide 0.7 ml, potassium carbonate 192 mg, potassium iodide 230 m
g and 340 mg of iodopropargyl bromide were added, and the mixture was stirred at room temperature overnight. After the reaction, the mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated potassium hydrogensulfate solution and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. 320 mg of the residue was purified by preparative thin layer chromatography (ethyl acetate-hexane) to obtain 6.6 mg of the desired product (I) (yield 5.5%). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.43 (3H, d, 4-CH ₃ ), 1.97 (3H,
_{s, 1-CH 3),} 4.80 (2H, s, -CH
_2- ), 4.88 (1H, q, -CH-), 7.43
(4H, m, aromatic nucleus H), 7.89 (2H, abq, oleophytic H)

Example 11 3- [2- (2-chlorophenyl) -1-propenyl-
ONN-azoxy] -2-propargyloxyimino-
Butane [compound (I): R ₁ = 2-chlorophenyl group,
R ₂ = methyl group, R ₃ = propargyl group]: 3- [2- (2-chlorophenyl) -1 obtained in Example 6
-Propenyl-ONN-azoxy] -2-hydroxyimino-butane (I) (24.4 mg) was dissolved in dimethylformamide (0.2 ml) to give propargyl bromide (0.08).
ml, potassium carbonate 60.8 mg, potassium iodide 7
1.8 mg was added and the mixture was stirred at room temperature for 13 hours. After the reaction
Water was added and the mixture was extracted with diethyl ether. The ether layer was washed with a saturated ammonium chloride solution and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. 39 mg of the residue were purified by preparative thin layer chromatography, 11.1 mg of the anti-isomer of the substituted oxime and 5.8 of the syn-isomer.
mg was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm anti-isomer 1.41 (3H, d, 4-CH ₃ ), 1.97 (3H,
_{s, 1-CH 3),} 2.45 (3H, d, 3'-C
_{H 3), 2.45 (1H,} t, acetylenic H), 4.
_{67 (2H, d, -CH 2} -), 4.84 (1H, q,
3-CH-), 6.86 (1H, q, 1'-H), 7.
20 to 7.33 (3H, m), 7.39 to 7.44 (1
H, m) syn - isomer 1.43 (3H, d, 4- CH 3), 1.87 (3H,
_{s, 1-CH 3),} 2.45 (3H, d, 3'-C
H ₃ ), 2.47 (1H, t, acetylenic H), 4.
_{66 (2H, d, -CH 2} -), 5.33 (1H, q,
3-CH-), 6.89 (1H, q, 1'-H), 7.
21-7.33 (3H, m), 7.39-7.45 (1
H, m)

Example 12 3- [2- (2-chlorophenyl) -1-propenyl-
Production of ONN-azoxy] -2- (3-iodopropargyloxyimino) -butane [Compound (I): R ₁ = 2-chlorophenyl group, R ₂ = methyl group, R ₃ = 3-iodopropargyl group]: 1) Anti-isomer 11. The anti-isomer of 3- [2- (2-chlorophenyl) -1-propenyl-ONN-azoxy] -2-propargyloxyimino-butane (I) obtained in Example 11. 1 mg was dissolved in 0.3 ml of methanol, and 0.01 N of 10N sodium hydroxide solution and 21.8 mg of iodine were sequentially added while stirring with ice cooling. After reacting for 1 hour, diethyl ether and 1M sodium thiosulfate were added, and the mixture was extracted with diethyl ether. The ether layer was washed with a saturated ammonium chloride solution and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue (16 mg) was purified by preparative thin layer chromatography (acetone-benzene) to obtain the target anti-isomer (13.4 mg). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.41 (3H, d, 4-CH ₃ ), 1.96 (3H,
_{s, 1-CH 3),} 2.45 (3H, d, 3'-C
_{H 3), 4.80 (2H,} s, OCH 2), 4.82
(1H, q, 3-CH-), 6.86 (1H, q, 1 '
-CH), 7.17 to 7.44 (4H, m)

(2) Syn-isomer 5. Syn-isomer of compound (I) obtained in Example 11.
8 mg was dissolved in 0.2 ml of methanol and stirred under ice cooling.
0.005 ml of a 10 N sodium hydroxide solution and 14.8 mg of iodine were sequentially added. After reacting for 1 hour, diethyl ether and 1M sodium thiosulfate were added, and the mixture was extracted with diethyl ether. The ether layer was washed with a saturated ammonium chloride solution and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue (8 mg) was purified by preparative thin layer chromatography (acetone-benzene) to obtain the target syn-isomer (13.4 mg). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.42 (3H, d, 4-CH ₃ ), 1.86 (3H,
_{s, 1-CH 3),} 2.47 (3H, d, 3'-C
H ₃ ), 4.98 (2H, s, OCH ₂ ), 5.32
(1H, q, 3-CH-), 6.89 (1H, q, 1 '
-CH-), 7.18 to 7.45 (4H, m)

Example 13 3- [2- (4- (3-Iodopropargyl) oxyphenyl) -1-propenyl-ONN-azoxy] -2-
Methoxyimino-butane [Compound (I): R ₁ = 4-
(3-iodopropargyl) oxyphenyl group, R ₂ =
R ₃ = methyl group]: 3 obtained in Example 1 (4)
46 mg of-[2- (4- (3-iodopropargyl) oxyphenyl) -1-propenyl-ONN-azoxy] -2-oxobutane (II) was dissolved in 1 ml of methanol, 8 mg of O-methylhydroxylamine hydrochloride was added, and the mixture was stirred at room temperature. With stirring, 0.1 ml of pyridine was added dropwise. 10
After stirring for a minute, part of the solvent was concentrated under reduced pressure and subjected to preparative thin-layer chromatography to obtain 23 mg of the target anti-methyloxime. Optical rotation +22.9
(C1, CHCl _3). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.41 (3H, d, 4-CH ₃ ), 1.93 (3H,
_{s, 1-CH 3),} 2.47 (3H, d, 3'-C
H ₃ ), 3.86 (3H, s, OCH ₃ ), 4.80
(1H, q, 3-CH-), 4.85 (2H, s, OC
H ₂ ), 6.97 (2H, m, aromatic nucleus H), 7.11
(1H, m, 1'-CH), 7.40 (2H, m, aromatic nucleus H)

Example 14 3- [4 '-(3-Iodopropargyl) oxystyryl-ONN-azoxy] -2-methoxyimino-butane [Compound (I): R ₁ = 4- (3-iodopropargyl) oxyphenyl] Group, R ₂ = hydrogen atom, R ₃ = methyl group]: 3- [4′-obtained in Example 4 (4)
(3-Iodopropargyl) oxystyryl-ONN-
Azoxy] -2-oxobutane (II) (193 mg) was dissolved in a mixed solution of methanol (4 ml) and dimethylformamide (1 ml) to give O-methylhydroxylamine hydrochloride (61 m).
g and 0.06 ml of pyridine were added, and the mixture was stirred at room temperature for 75 minutes. After the reaction, the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated potassium hydrogen sulfate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to obtain 122.9 mg of the anti-isomer of the desired product (I). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.41 (3H, d, 4-CH ₃ ), 1.92 (3H,
_{s, 1-CH 3),} 3.86 (3H, s, O-C
_{H 3), 4.86 (2H,} s, -CH 2 -), 4.86
(1H, q, -CH-), 7.22 (4H, abq, aromatic nucleus H), 7.64 (2H, abq, olefinic H)

Example 15 2-Carboxymethoxyimino-3- [4 '-(3-
Production of iodopropargyl) oxystyryl-ONN-azoxy] -butane [Compound (I): R ₁ = 4- (3-propargyl) oxyphenyl group, R ₂ = hydrogen atom, R ₃ = carboxylmethyl group]: Example 4 20 mg of 3- [4 '-(3-iodopropargyl) oxystyryl-ONN-azoxy] -2-oxobutane obtained in (4)
Methanol-dimethylformamide (5: 1) 0.2
0.01 ml of pyridine and 14 m of O-carboxymethylhydroxylamine hydrochloride under stirring at room temperature.
g was added. After reacting for 30 minutes, the mixture was diluted with diethyl ether, and the ether layer was washed successively with 1N hydrochloric acid, water and saturated brine. The ether layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to obtain 19 mg of the desired product (I) (anti-isomer: syn-isomer 3: 1 mixture). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.41, 1.50 (3 H, d, 4-CH ₃ ), 1.7
9,2.01 (3H, s, 1- CH 3), 4.64 (2
H, s, OCH ₂ CO), 4.86 (2H, s, OCH
₂ C), 6.98, 7.46 (each 2H, d, aromatic nucleus H), 7.51, 7.77 (each 1H, d,
Olefinity H)

Example 16 3- (6-Iodo-1-hexen-5-yl-ONN-
Azoxy) -2-hydroxyiminobutane [compound (I): R ₁ = 4-iodo-3-butynyl group, R ₂ = R
₃ = H]: (1) 3- (Methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) 200 obtained in Reference Example
Dissolve mg in 2 ml anhydrous tetrahydrofuran, -40
Cooled to ° C. 0.9 ml of lithium diisopropylamide (1.55M hexane solution) was added dropwise to this, and 20
Stir for minutes. 5-iodo-4-pentinal 2
A solution of 90 mg of anhydrous tetrahydrofuran in 2 ml was gradually added dropwise. After stirring for 30 minutes, the reaction was stopped by adding a saturated ammonium chloride solution under ice cooling. The reaction mixture was extracted with diethyl ether, the ether layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- (2-
Hydroxy-6-iodo-5-hexynyl-ONN-azoxy) -2,2-propylenedioxybutane (V) 3
Obtained 00 mg. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.25, 1.28 (3H, d, 4-CH ₃ ), 1.5
0,1.53 (3H, s, 1- CH 3)

(2) 270 mg of the hydroxy compound (V) obtained in (1) above was dissolved in 1 ml of anhydrous tetrahydrofuran, 0.16 ml of triethylamine and 0.08 ml of methanesulfonium chloride were added under ice cooling, and the mixture was stirred for 20 minutes. After the reaction, saturated sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with diethyl ether. 1 ether layer
The extract was washed with normal hydrochloric acid, water, saturated sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained oily substance was dissolved in 1 ml of anhydrous tetrahydrofuran, 0.5 ml of 1,8-diazabicyclo [5.4.0] -7-undecene was added under ice cooling, and the mixture was stirred for 1 hour. After the reaction
Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The ether layer was washed with 1N hydrochloric acid, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- (6-iodo-1-
63 mg of hexen-5-yl-ONN-azoxy) -2,2-propylenedioxybutane (III) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.17 (3H, d, 4-CH ₃ ), 1.47 (3H,
_{s, 1-CH 3),} 1.57~1.66 (1H, m),
1.74-1.89 (1H, m), 2.38-2.48
(2H, m), 2.55 (2H, dt, 3'-CH
_2- ), 3.88 to 3.99 (4H, m), 4.65
(1H, q), 6.92 to 7.08 (2H, m)

(3) 10 mg of the propylenedioxy derivative (III) obtained in (2) above was dissolved in 0.5 ml of acetonitrile, and 26 mg of ferric chloride-silica gel was added under ice cooling, and the mixture was stirred at room temperature for 20 minutes. . After the reaction, silica gel was filtered off from the reaction solution and diluted with diethyl ether. The ether layer was purified with saturated sodium hydrogen carbonate, a saturated ammonium chloride solution, and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, 3- (6-iodo-1-hexen-5-yl-ONN-azoxy) -2-oxobutane (II) 8 mg.
Got ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.47 (3H, d, 4-CH ₃ ), 2.19 (3H,
_{s, 1-CH 3),} 2.44~2.50 (2H, m),
2.54 to 2.60 (2H, dt), 4.61 (1H,
q), 7.02 to 7.06 (2H, m)

(4) 21 mg of the oxo compound obtained in (3) above was added to dimethylformamide-methanol (1:
5) Dissolve in 0.5 ml, add 11 mg of hydroxylamine hydrochloride and 0.015 ml of pyridine at room temperature,
Stir for minutes. After the reaction, the reaction solution was diluted with diethyl ether, and the ether layer was washed with 0.5N hydrochloric acid, a saturated sodium hydrogen carbonate solution, a saturated ammonium chloride solution, and a saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 9 mg of anti-isomer and 2 mg of syn-isomer of the target product (I).
Got ¹ H-NMR value: δ CDCl ₃ , TMS, ppm anti-isomer 1.38 (3H, d, 4-CH ₃ ), 1.95 (3H,
_{s, 1-CH 3),} 2.41~2.47 (2H, m),
2.53 to 2.62 (2H, dt), 4.79 (1H,
q), 7.00~7.03 (2H, m ) syn - isomer 1.42 (3H, d, 4- CH 3), 1.77 (3H,
_{s, 1-CH 3),} 2.42~2.48 (2H, m),
2.54 to 2.62 (2H, dt), 5.37 (1H,
q), 7.01 to 7.04 (2H, m)

Example 17 2-Hydroxyimino-3- [4 '-(4-iodo-3)
-Butynyl) styryl-ONN-azoxy] -butane [Compound (I): R ₁ = 4- (4-iodo-3-butynyl) phenyl group, R ₂ = R ₃ = hydrogen atom]: (1) Reference 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) obtained in the example 60 m
g was dissolved in anhydrous tetrahydrofuran 0.7 ml, -4
Cooled to 0 ° C. 0.26 ml of lithium diisopropylamide (1.56M hexane solution) was added dropwise to this, and 2
Stir for 0 minutes. To this, p- (3-butynyl) benzaldehyde 50 mg anhydrous tetrahydrofuran 0.5 ml
The above solution was gradually added dropwise. After stirring for 30 minutes, the reaction was stopped by adding a saturated ammonium chloride solution under ice cooling. The reaction mixture was extracted with diethyl ether, the ether layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- [2-hydroxy-2- (4'-
(3-Butynyl) phenyl) -ethyl-ONN-azoxy] -2,2-propylenedioxybutane (V ') 35
mg was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.10, 1.16 (3H, d, 4-CH ₃ ), 1.4
3,1.44 (3H, s, 1- CH 3), 1.57~
1.68 (1H, m), 1.80 to 1.85 (1H,
m), 1.97 (1H, t), 2.47 (2H, d)
t), 2.84 (2H, t), 3.88 to 3.97 (4
H, m), 4.35 to 4.40 (2H, m), 4.56
-4.61 (1H, m), 5.23-5.35 (1H,
m), 7.25 to 7.38 (4H, m)

(2) 35 mg of the hydroxy compound (V ') obtained in the above (1) was added to anhydrous tetrahydrofuran 0.2
Dissolve in ml and under ice cooling, triethylamine 0.11 ml
And 0.06 ml of methanesulfonyl chloride,
Stir for minutes. After the reaction, saturated sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with diethyl ether. The ether layer was washed with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure.
The obtained oily substance was dissolved in 0.2 ml of anhydrous tetrahydrofuran, and 1,8-diazabicyclo [5.4.
0] -7-Undecene (0.076 ml) was added, and the mixture was stirred for 10 minutes. After the reaction, water was added to the reaction solution and the mixture was extracted with diethyl ether. The ether layer was washed with 1N hydrochloric acid, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- [4 '-(3-butynyl) styryl-ONN-
Azoxy] -2,2-propylenedioxybutane (III
′) 18 mg was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.22 (3H, d, 4-CH ₃ ), 1.51 (3H,
_{s, 1-CH 3),} 1.56~1.66 (1H, m),
1.82 to 1.87 (1H, m), 1.99 (1H,
t,), 2.50 (2H, dt, 3'-CH 2 -),
2.86 (1H, t), 3.93 to 4.01 (4H,
m), 4.72 (1H, q), 7.26 (2H, d),
7.43 (2H, d), 7.63 (1H, d), 7.7
8 (1H, d)

(3) 18 mg of the butynyl compound (III ') dehydrated product obtained in the above (2) was dissolved in 0.8 ml of methanol, 102 caustic soda (0.02 ml) and iodine (28 mg) were added under ice cooling, and then room temperature. And stirred for 20 minutes. After the reaction, saturated sodium thiosulfate solution was added, and the mixture was extracted with diethyl ether. The ether layer is 1N hydrochloric acid,
The extract was washed with saturated sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- [4 '-(4-
Iodo-3-butynyl) styryl-ONN-azoxy]
22 mg of -2,2-propylenedioxybutane (III) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.22 (3H, d, 4-CH ₃ ), 1.51 (3H,
_{s, 1-CH 3),} 1.56~1.66 (1H, m),
1.82 to 1.87 (1H, m), 2.65 (2H,
t), 2.85 (1H, t), 3.93 to 4.01 (4
H, m), 4.71 (1H, q), 8.23 (2H,
d), 7.43 (2H, d), 7.63 (1H, d),
7.78 (1H, d)

(4) 22 mg of the propylenedioxy compound (III) obtained in the above (3) was added to 0.5 m of acetonitrile.
Dissolve in 1 and under ice cooling, ferric chloride-silica gel 47 mg
Was added and the mixture was stirred at room temperature for 1 hour. After the reaction, silica gel was filtered off from the reaction solution and diluted with diethyl ether. The ether layer was purified with saturated sodium hydrogen carbonate, a saturated ammonium chloride solution, and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 13 mg of 3- [4 '-(4-iodo-3-butynyl) styryl-ONN-azoxy] -2-oxobutane (II). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.44 (3H, d, 4-CH ₃ ), 2.14 (3H,
_{s, 1-CH 3),} 2.59 (2H, t), 2.79
(2H, d), 4.62 (1H, q), 7.18 (2
H, d), 7.38 (2H, d), 7.56 (1H,
d), 7.74 (1H, d)

(5) 13 mg of the oxo compound (II) obtained in (4) above was dissolved in 0.2 ml of dimethylformamide-methanol (1: 5), and 5 mg of hydroxylamine hydrochloride and 0.007 ml of pyridine were added at room temperature. hand,
Stir for 30 minutes. After the reaction, the reaction solution was diluted with diethyl ether, and the ether layer was washed with 1N hydrochloric acid, a saturated sodium hydrogen carbonate solution, a saturated ammonium chloride solution, and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, 3-
[4 '-(4-iodo-3-butynyl) styryl-ON
13 mg of N-azoxy] -2-oxobutane (II) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.44 (3H, d, 4-CH ₃ ), 2.14 (3H,
_{s, 1-CH 3),} 2.59 (2H, t), 2.79
(2H, d), 4.62 (1H, q), 7.18 (2
H, d), 7.38 (2H, d), 7.56 (1H,
d), 7.74 (1H, d)

(5) 13 mg of the oxo compound (II) obtained in (4) above was dissolved in 0.2 ml of dimethylformamide-methanol (1: 5), and 5 mg of hydroxylamine hydrochloride and 0.007 ml of pyridine were added at room temperature. hand,
Stir for 30 minutes. After the reaction, the reaction solution was diluted with diethyl ether, and the ether layer was washed with 1N hydrochloric acid, a saturated sodium hydrogen carbonate solution, a saturated ammonium chloride solution, and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 6 mg of anti-isomer and 3 mg of syn-isomer of the target product (I).
Got ¹ H-NMR value: δ CDCl ₃ , TMS, ppm anti-isomer 1.35 (3H, d, 4-CH ₃ ), 1.91 (3H,
_{s, 1-CH 3),} 2.58 (2H, t), 2.78
(2H, t), 4.80 (1H, q), 7.17 (2
H, d), 7.37 (2H, d), 7.51 (1H,
d), 7.73 (1H, d ) syn - isomer 1.46 (3H, d, 4- CH 3), 1.80 (3H,
_{s, 1-CH 3),} 2.66 (2H, t), 2.86
(2H, t), 5.44 (1H, q), 7.25 (2
H, d), 7.45 (2H, d), 7.59 (1H,
d), 7.81 (1H, d)

Example 18 3- (1,3,5-octatrienyl-ONN-azoxy) -2-hydroxyiminobutane [Compound (I): R
₁ = 2,4-hexadiene, R ₂ = R ₃ = hydrogen production atom]: (1) 3 obtained in Reference Example (methyl -ONN- azoxy) -2,2-propylene dioxy butane 500mg tetrahydrofuran It was dissolved in 3 ml, and a hexane solution of lithium diisopropylamide (1.3 equivalents) was added dropwise under stirring with ice cooling. After stirring for 30 minutes, a solution of trans, trans, 352 mg of 2,4-heptadienal in 5 ml of tetrahydrofuran was added dropwise, and the mixture was further stirred for 1 hour.
The reaction was stopped by adding 10 ml of a saturated ammonium chloride solution, and the mixture was extracted with diethyl ether. The ether layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 400 mg of 3- (2-hydroxy-3,5-octadienyl-ONN-azoxy) -2,2-propylenedioxybutane (V). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.00 (3H, t, 8′-CH ₃ ), 1.13, 1.
16 (3H, d, 4- CH 3), 1.46 (3H, s,
_{1-CH 3), 2.10 (} 2H, m, 7'-CH
_2- ), 4.10 to 4.40 (2H, m), 4.52
4.70 (1H, m, 3-CH-), 5.46-6.4
8 (4H, m, olefinic H)

(2) 362 mg of the hydroxy compound (V) obtained in (1) above was dissolved in 0.8 ml of pyridine,
0.15 ml of methanesulfonium chloride was added, and the mixture was stirred at room temperature for 30 minutes. The reaction is then cooled to 0 ° C,
0.9 ml of 1,8-diazabicyclo [5.4.0] -7-undecene was added, and the mixture was further stirred for 30 minutes. After the reaction, the reaction solution was poured into a mixed solution of 20 ml of diethyl ether and 10 ml of water and extracted with diethyl ether. The ether layer was washed successively with 0.4N potassium hydrogensulfate solution, water, saturated sodium hydrogencarbonate solution, water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- (1,3,5
225 mg of -octatrienyl-ONN-azoxy) -2,2-propylenedioxybutane (III) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.04 (3 H, t, 8′-CH ₃ ), 1.18 (3
_{H, d, 4-CH 3} ) 1.48 (3H, s, 1-C
_{H 3), 2.16 (2H,} m, 7'-CH 2 -), 4.
68 (2H, m, 3-CH-), 5.99 (1H, d
t, 6'-CH =), 6.18 (1H, dd, 5 '= C
H-), 6.29 (1H, dd, 4'-CH =), 6.
60 (1H, dd, 3 '= CH-), 7.15 (1H,
d, 1 '= CH-), 7.40 (1H, dd, 2'-C
H =)

(3) 58 mg of the propylenedioxy compound (III) obtained in (2) above was dissolved in 2 ml of acetonitrile, 115 mg of ferric chloride-silica gel was added, and the mixture was stirred at room temperature for 5 minutes. After the reaction, the mixture was diluted with diethyl ether, the ether layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue (47 mg) was dissolved in methanol (2 ml), hydroxylamine hydrochloride (10 mg) and 1N pyridine-methanol (0.15 ml) were added, and the mixture was stirred at room temperature for 5 min. After the reaction, the mixture was diluted with diethyl ether, and the ether layer was washed with water. The ether layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue (21 mg) was purified by silica gel thin layer chromatography to obtain the anti-isomer (10 mg) and the syn-isomer (8 mg) of the desired product (I). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm anti-isomer 1.04 (3 H, t, 8′-CH ₃ ), 1.38 (3
_{H, d, 4-CH 3} ), 1.95 (3H, s, 1-CH
_{3), 2.18 (2H, m} , 7'-CH 2 -), 4.8
3 (1H, q, 3-CH-), 5.95 to 6.30 (3
H, m, olefinic H), 6.56 (1H, dd, olefinic H), 7.09 (1H, d, olefinic H), 7.37 (1H, dd, olefinic H) syn-isomer body 1.04 (3H, t, 8'- CH 3), 1.42 (3
_{H, d, 4-CH 3} ), 1.76 (3H, s, 1-CH
_{3), 2.18 (2H, m} , 7'-CH 2 -), 5.3
9 (1H, q, 3-CH-), 5.95 to 6.30 (3
H, m, olefinic H), 6.60 (1H, dd, olefinic H), 7.11 (1H, d, olefinic H), 7.43 (1H, dd, olefinic H)

Example 19 3- (2-Phenyl-1-propenyl-ONN-azoxy) -2-hydroxyiminobutane [Compound (I): R
₁ = phenyl group, R ₂ = methyl group, R ₃ = hydrogen atom] 1: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI ) 376
mg was dissolved in 5 ml of tetrahydrofuran, and a hexane solution of lithium diisopropylamide (1.3 equivalents) was added dropwise under stirring with ice cooling. After stirring for 30 minutes, 5 ml of a tetrahydrofuran solution containing 300 mg (1.5 equivalents) of acetophenone was added dropwise. After the dropping, the mixture was further stirred for 1 hour, and 5 ml of a saturated ammonium chloride solution was added to stop the reaction. The reaction solution was extracted with diethyl ether, and the ether layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3- (2-hydroxy-2-
403 mg of phenylpropyl-ONN-azoxy) -2,2-propylenedioxybutane (V) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 0.70, 1.05 (3H, d, 4-CH ₃ ), 1.2.
4,1.36 (3H, s, 1- CH 3), 1.55 (3
_{H, s, 3'-CH 3} ), 4.34~4.45 (1H,
m, 3-CH-), 4.40 to 4.60 (2H, m,
_{1'-CH 2 -), 7.20~7.36} (3H, m, arom H), 7.45~7.54 (2H, m , arom H)

(2) 403 mg of the hydroxy compound (V) obtained in (1) above was dissolved in 2 ml of pyridine, 0.29 ml of thionyl chloride was added, and the mixture was stirred for 2 hours under ice cooling. After the reaction, the mixture was poured into ice water and extracted with diethyl ether. The ether layer was washed with a saturated sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. Dissolve 300 mg of the residue in 2 ml of benzene, and add 1,8
-Diazabicyclo [5.4.0] -7-undecene 0.
27 ml was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was purified by subjecting it to column chromatography on silica gel to give 3- (2-phenyl-1-propenyl-ONN-).
Azoxy) -2,2-propylenedioxybutane (III)
104 mg was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.23 (3H, d, 4-CH ₃ ), 1.51 (3H,
_{s, 1-CH 3),} 2.48 (3H, d, 3'-C
_{H 3), 4.71 (1H,} q, 3-CH -), 7.12
(1H, q, 1 '= CH-), 7.36 to 7.46 (5
H, m, aromatic nucleus H)

(3) 40 mg of the propylenedioxy compound (III) obtained in (2) above is dissolved in 2 ml of acetonitrile, 40 mg of ferric chloride-silica gel is added, and the mixture is stirred at room temperature for 1 hour. After the reaction, the silica gel was removed, the solvent was concentrated under reduced pressure, the residue was dissolved in 2 ml of methanol, and 14 mg of hydroxylamine hydrochloride and 0.02 ml of pyridine were added.
Was added and stirred at room temperature for 1 hour. After the reaction, the solvent was concentrated under reduced pressure and purified by silica gel thin layer chromatography to obtain 24 mg of the anti-isomer and 8 mg of the syn-isomer of the target product (I). ¹ H-NMR value: δ CDC
l _3, TMS, ppm anti - isomer 1.42 (3H, d, 4- CH 3), 1.98 (3H,
_{s, 1-CH 3),} 2.49 (3H, d, 3'-C
_{H 3), 4.83 (1H,} q, 3-CH), 7.13
(1H, q, 1 '= CH-), 7.36 to 7.45 (5
H, m, arom H) syn - isomer 1.46 (3H, d, 4- CH 3), 1.82 (3H,
_{s, 1-CH 3),} 2.53 (3H, d, 3'-C
_{H 3), 5.41 (1H,} q, 3-CH), 7.16
(1H, q, 1 '= CH-), 7.37 to 7.45 (5
H, m, aromatic nucleus H)

Example 20 3- (2-Phenyl-1-propenyl-ONN-azoxy) -2- (3-iodopropargyloxyimino)-
Production of butane [compound (I): R ₁ = phenyl group, R ₂ = methyl group, R ₃ = 3-iodopropargyl group]: 3- (2-phenyl-1-) obtained in Example 19 (2) 26.3 mg of propenyl-ONN-azoxy) -2,2-propylenedioxybutane (III) was added to 2 ml of acetonitrile.
, Ferric chloride-silica gel 90 mg, and the mixture was stirred at room temperature for 45 minutes. After the reaction, dilute with ethyl acetate,
The insoluble material was filtered off, the ethyl acetate layer of the filtrate was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. This one
It was dissolved in ethanol (ml) and added dropwise to a solution of hydroxylamine prepared in the same manner as in Example 8 at room temperature with stirring.
After reacting overnight, the mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue (35.9 mg) was purified by preparative thin layer chromatography, and the target compound (I) (anti-isomer: syn-isomer 5: 1 mixture) 14.5 was used.
mg (yield 38.9%) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm (identifiable on chart) anti-isomer 1.42 (3H, d, 4-CH ₃ ), 1.96 (3H,
_{s, 1-CH 3),} 2.50 (3H, d, 3'-C
_{H 3), 4.80 (2H,} s, -CH 2 -), 4.82
(1H, q, -CH-), 7.11 (1H, d, olefinic H), 7.42 (5H, m, aromatic nucleus H) syn-isomer 1.43 (3H, d, 4-CH) ₃ ) 1.85 (3H,
_{s, 1-CH 3),} 2.52 (3H, d, 3'-C
_{H 3), 4.81 (2H,} s, -CH 2 -), 5.30
(1H, q, -CH-), 7.14 (1H, d, olefinic H), 7.42 (5H, m, aromatic nucleus H)

Example 21 3- [2- (4-chlorophenyl) -1-propenyl-
Production of ONN-azoxy] -2-hydroxyiminobutane [Compound (I): R ₁ = 4-chlorophenyl, R ₂ = methyl group, R ₃ = hydrogen atom]: (1) 3- ( Methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) 376
mg was dissolved in 5 ml of tetrahydrofuran, and a hexane solution of lithium diisopropylamide (1.3 equivalents) was added dropwise under stirring with ice cooling. After stirring for 30 minutes, p
3 ml of a tetrahydrofuran solution containing 464 mg (1.5 equivalents) of -chloroacetophenone was added dropwise. After the dropping, the mixture was further stirred for 1 hour, and 5 ml of a saturated ammonium chloride solution was added to stop the reaction. The reaction solution was extracted with diethyl ether, and the ether layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 436 mg of diastereomers of 3- [2-hydroxy-2- (4-chlorophenyl) propyl-ONN-azoxy] -2,2-propylenedioxybutane (V). It was ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 0.74, 1.05 (3 H, d, 4-CH ₃ ), 1.2.
4,1.36 (3H, s, 1- CH 3), 1.55 (3
_{H, s, 3'-CH 3} ), 4.20~4.44 (1H,
m, 3-CH-), 4.46 (2H, dd, 1'-CH
_2- ), 7.20 to 7.32 (2H, m, aromatic nucleus H),
7.34 to 7.44 (2H, m, aromatic nucleus H)

(2) 436 mg of the hydroxy compound (V) obtained in (1) above is dissolved in 2 ml of pyridine, 0.29 ml of thionyl chloride is added, and the mixture is stirred under ice cooling for 2 hours. After the reaction, the mixture was poured into ice water and extracted with diethyl ether. The ether layer is washed with saturated sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. 342 mg of the residue was dissolved in 2 ml of benzene, and 1,8
-Diazabicyclo [5.4.0] -7-undecene 0.
Add 28 ml and stir at room temperature for 1 hour. After the reaction, the reaction solution was purified by subjecting it to silica gel column chromatography to obtain 84 mg of 3- [2- (4-chlorophenyl) -1-propenyl-ONN-azoxy] -2,2-propylenedioxybutane (III). .. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.22 (3H, d, 4-CH ₃ ), 1.50 (3H,
_{s, 1-CH 3),} 2.44 (3H, d, 3'-C
_{H 3), 4.68 (1H,} q, 3-CH -), 7.07
(1H, q, 1 '= CH-), 7.24 (4H, m, aromatic nucleus H)

(3) 40 mg of the propylenedioxy compound (III) obtained in (2) above was dissolved in 2 ml of acetonitrile, 40 mg of ferric chloride-silica gel was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the silica gel was removed, the solvent was concentrated under reduced pressure, the residue was dissolved in 2 ml of methanol, and 14 mg of hydroxylamine hydrochloride and 0.02 ml of pyridine were added.
Was added and stirred at room temperature for 1 hour. After the reaction, the solvent was concentrated under reduced pressure and purified by silica gel thin layer chromatography to obtain 25 mg of the anti-isomer and 9 mg of the syn-isomer of the target compound (I). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm anti-isomer 1.42 (3H, d, 4-CH ₃ ), 1.96 (3H,
_{s, 1-CH 3),} 2.43 (3H, d, 3'-C
_{H 3), 4.82 (1H,} q, 3-CH -), 7.11
(1H, q, 1 '= CH-), 7.37 (5H, br
s, arom H) syn - isomer 1.45 (3H, d, 4- CH 3), 1.82 (3H,
_{s, 1-CH 3),} 2.50 (3H, d, 3'-C
_{H 3), 5.40 (1H,} q, 3-CH -), 7.14
(1H, q, 1 '= CH-), 7.37 (5H, br
s, aromatic nucleus H)

Example 22 3- [2- (4-Methoxyphenyl) -1-propenyl-ONN-azoxy] -2-hydroxyiminobutane [Compound (I): R ₁ = 4-methoxyphenyl group, R ₂
= Methyl group, R ₃ = hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) 567 obtained in Reference Example
mg was dissolved in 7 ml of tetrahydrofuran, and a hexane solution of lithium diisopropylamide (1.3 equivalents) was added dropwise under stirring with ice cooling. After stirring for 30 minutes, p
5 ml of a tetrahydrofuran solution of 495 mg (1.1 eq) of methoxyacetophenone is added dropwise. After dropping, the mixture was stirred for 1 hour, and 10 ml of saturated ammonium chloride solution was added.
Was added to stop the reaction. The reaction solution was extracted with ethyl acetate, and the ethyl acetate layer was washed with 0.4 N sodium hydrogen sulfate solution and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- [2-hydroxy-2- (4-methoxyphenyl) -propyl-ONN-azoxy] -2,
675 mg of diastereomers of 2-propylenedioxybutane (V) were obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 0.76, 1.07 (3 H, d, 4-CH ₃ ), 1.2.
7,1.28 (H, s, 1- CH 3), 1.55 (3
_{H, s, 3'-CH 3} ), 3.79 (3H, s, -OC
_{H 3), 4.30~4.60 (3H,} m, 3-CH-a
nd1′-CH ₂ —), 6.60 to 6.92 (2H,
m, aromatic nucleus H), 7.34 to 7.44 (2H, m, aromatic nucleus H)

(2) 202 mg of the hydroxy compound (V) obtained in (1) above was dissolved in 6 ml of pyridine, 1.2 mg of thionyl chloride was added, and the mixture was stirred for 2 hours under ice cooling. After the reaction, the mixture was poured into ice water and extracted with diethyl ether. The ether layer was washed with a saturated sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. 111 mg of the residue was dissolved in benzene,
0.1 ml of 8-diazabicyclo [5.4.0] -7-undecene was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was purified by subjecting to silica gel column chromatography to obtain 17 mg of 3- [2- (4-methoxyphenyl) -1-propenyl-ONN-azoxy] -2,2-propylenedioxybutane (III). Obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.22 (3H, d, 4-CH ₃ ), 1.51 (3H,
_{s, 1-CH 3),} 2.46 (3H, d, 3'-C
_{H 3), 3.84 (3H,} s, -OCH 3), 4.74
(1H, q, 3-CH-), 6.86 to 6.98 (2
H, m, aromatic nucleus H), 7.15 (1H, q, 1 '= CH
-), 7.34 to 7.46 (2H, m, aromatic nucleus H)

(3) 30 mg of the propylenedioxy compound (III) obtained in (2) above was dissolved in 2 ml of acetonitrile, 3 mg of ferric chloride-silica gel was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was diluted with diethyl ether, and the ether layer was washed with water. The ether layer was concentrated under reduced pressure, dissolved in 2 ml of methanol, and added with 10 mg of hydroxylamine hydrochloride and 0.02 ml of pyridine,
The mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was concentrated under reduced pressure and purified by silica gel thin layer chromatography to obtain 15 mg of the anti-isomer and 6 mg of the syn-isomer of the target compound (I). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm anti-isomer 1.42 (3H, d, 4-CH ₃ ), 1.98 (3H,
_{s, 1-CH 3),} 2.46 (3H, d, 3'-C
_{H 3), 4.83 (1H,} q, 3-CH -), 6.86
~ 6.95 (2H, m, aromatic nucleus H), 7.13 (1H,
q, 1 '= CH-), 7.35 to 7.45 (2H, m,
Arom H) syn - isomer 1.45 (3H, d, 4- CH 3), 1.82 (3H,
_{s, 1-CH 3),} 2.52 (3H, d, 3'-C
_{H 3), 5.41 (1H,} q, 3-CH -), 6.88
(2H, m, aromatic nucleus H), 7.18 (1H, q, 1 '=
CH-), 7.36 to 7.44 (2H, m, aromatic nucleus H)

Example 23 3- (Styryl-ONN-azoxy) -2- (3-iodopropargyloxyimino) -butane [Compound (I): R ₁ = phenyl group, R ₂ = hydrogen atom, R ₃ = 3]
-Iodopropargyl group]: 3- (styryl-ONN-azoxy) -2,2-propylenedioxybutane 90 mg obtained in Example 9 (2)
Was dissolved in 6 ml of acetonitrile, 270 mg of ferric chloride-silica gel was added, and the mixture was stirred at room temperature for 40 minutes. After the reaction, the reaction mixture was diluted with ethyl acetate and the insoluble material was filtered off, the ethyl acetate layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. This residue was dissolved in 2 ml of ethanol. This is processed in the same manner as the latter half of Example 20,
Target compound (I) (anti-isomer: syn-isomer 4: 1)
99.1 mg) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm (identifiable on chart) Anti-isomer 1.42 (3H, d, 4-CH ₃ ), 1.96 (3H,
_{s, 1-CH 3),} 4.80 (2H, s, -CH
_2- ), 4.87 (1H, q, -CH-), 7.45
(5H, m, arom H), 7.69 (2H, abq , olefinic H) syn - isomer 1.44 (3H, d, 4- CH 3), 1.83 (3H,
_{s, 1-CH 3),} 4.79 (2H, s, -CH
_2- ), 5.35 (1H, q, -CH-), 7.45
(5H, m, aromatic nucleus H), 7.69 (2H, abq, olefinic H)

Example 24 3- [2 '-(3-Iodopropargyloxy) styryl-ONN-azoxy] -2-hydroxyiminobutane [Compound (I): R ₁ = 2- (3-iodopropargyloxy) phenyl] Group, R ₂ = R ₃ = hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) 317 obtained in Reference Example
mg was dissolved in 3 ml of tetrahydrofuran, and a hexane solution of lithium diisopropylamide (1.3 equivalents) was added dropwise under stirring with ice cooling. After stirring for 30 minutes, -30 ° C
After cooling to 0 ° C, 3 ml of a tetrahydrofuran solution containing 404 mg (1.5 equivalents) of o-propargyloxybenzaldehyde was added dropwise. After dropping, stir for another 50 minutes,
The reaction was stopped by adding 3 ml of saturated ammonium chloride solution. The reaction solution was extracted with diethyl ether, and the ether layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue (863 mg) was purified by silica gel column chromatography to give 3- [2-hydroxy-2].
-(2'-Propargyloxy) phenyl-ethyl-O
335 mg of the diastereomer of NN-azoxy] -2,2-propylenedioxybutane (V) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.03, 1.27 (3H, d, 4-CH ₃ ), 1.4
6, 1.47 (3H, s, 1-CH ₃ ), 2.51 (1
H, t, ≡CH), 3.77~4.05 (4H, m, ketal _{-OCH 2 - × 2), 4.45~4.81} (5
H, m), 6.98 to 7.12 (2H, m, aromatic nucleus H), 7.32 (1H, m, aromatic nucleus H), 7.62 (1
H, m, aromatic nucleus H)

(2) 240 mg of the hydroxy compound (V) obtained in (1) above was dissolved in 1.4 ml of pyridine,
0.4 ml (6 equivalents) of acetic anhydride was added, and the mixture was stirred at room temperature for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in 1 ml of tetrahydrofuran. 1,8-diazabicyclo [5.4.0] -7-undecene 0.13 m
1 (5 equivalents) was added, and the mixture was heated and stirred at 40 ° C. for 3.5 hours. After the reaction, 10 ml of diethyl ether and 4 ml of 1N hydrochloric acid were added to the reaction solution, and the mixture was extracted with ether. The ether layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 204 mg of 3- [2'-propargyloxystyryl-ONN-azoxy] -2,2-propylenedioxybutane (III '). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.22 (3H, d, 4-CH ₃ ), 1.51 (3H,
s, 1-CH ₃ ), 2.53 (1H, t, ≡CH),
4.73 (1H, q, 3-CH-), 4.82 (2H,
_{d, OCH 2), 6.98~7.09 (} 2H, m, arom H), 7.33~7.47 (2H, m , arom H),
7.83 (1H, d, = CH-), 8.00 (1H,
d, -CH =)

(3) 48 mg of the propargyloxy compound (III ') obtained in the above (2) was added to 1.5 m of methanol.
Dissolve in 1 and under ice cooling, 74 mg (2 equivalents) of iodine and 10
0.058 ml of a normal sodium hydroxide solution was added, the ice bath was removed, and the mixture was stirred for 20 minutes. After the reaction, 0.5 ml of a 2N sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with diethyl ether. The ether layer was washed with 1N hydrochloric acid, saturated sodium hydrogen carbonate solution, and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- [2 '-(3-iodopropargyloxy) styryl-ONN-azoxy]-
44 mg of 2,2-propylenedioxybutane (III) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.22 (3H, d, 4-CH ₃ ), 1.51 (3H,
_{s, 1-CH 3),} 4.73 (1H, q, 3-CH
-), 4.95 (2H, d , OCH 2), 6.09~
7.07 (2H, m, aromatic nucleus H), 7.33 to 7.47
(2H, m, aromatic nucleus H), 7.82 (1H, d, = CH
-), 7.98 (1H, d, -CH =)

(4) 145 mg of the propylenedioxy compound (III) obtained in (3) above was dissolved in 5 ml of acetone, 290 mg of ferric chloride-silica gel was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, silica gel was removed, the mixture was diluted with diethyl ether, the ether layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of dimethylformamide-methanol (1: 5), 35 mg (1.5 equivalents) of hydroxylamine hydrochloride and 0.05 ml of pyridine were added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 94 mg of the anti-isomer and 20 mg of the syn-isomer of the target product (I). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm anti-isomer 1.42 (3H, d, 4-CH ₃ ), 1. 8 (3H,
_{s, 1-CH 3),} 4. 0 (1H, q, 3-CH
-), 4.95 (2H, s , OCH 2), 6.99~
7.08 (2H, m, aromatic nucleus H), 7.34 to 7.48
(2H, m, aromatic nucleus H), 7.80 (1H, d, 1 '=
CH -), 8.00 (1H, d, 2'-CH =) syn - isomer 1.47 (3H, d, 4- CH 3), 1.80 (3H,
_{s, 1-CH 3),} 4.96 (1H, q, 3-CH
-), 5.44 (2H, s , OCH 2), 7.00~
7.09 (2H, m, aromatic nucleus H), 7.34 to 7.49
(2H, m, aromatic nucleus H), 7.82 (1H, d, 1 '=
CH-), 8.00 (1H, d, 2'-CH =)

Example 25 3- [3 '-(3-Iodopropargyloxy) styryl-ONN-azoxy] -2-hydroxyiminobutane [Compound (I): R ₁ = 3- (3-Iodopropargyloxy) phenyl] Group, R ₂ = R ₃ = hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) 240 obtained in Reference Example
mg was dissolved in 3 ml of tetrahydrofuran, and a hexane solution of lithium diisopropylamide (1.3 equivalents) was added dropwise under stirring with ice cooling. After stirring for 30 minutes, -10 ° C
After cooling to 2.1 ml, 2.1 ml of a tetrahydrofuran solution containing 305 mg (1.5 equivalents) of m-propargyloxybenzaldehyde was added dropwise. After the dropping, the mixture was stirred for another 30 minutes, and 3 ml of a saturated ammonium chloride solution was added to stop the reaction. The reaction solution was extracted with diethyl ether, the ether layer was washed with water and saturated saline, and then dried with sodium sulfate,
Concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- [2-hydroxy-2-
254 mg of the diastereomer of (2 '-(3-propargyloxy) phenyl) ethyl-ONN-azoxy] -2,2-propylenedioxybutane (V) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.18, 1.22 (3H, d, 4-CH ₃ ), 1.4
7,1.48 (3H, s, 1- CH 3), 2.53,
2.54 (1H, t, ≡CH), 4.71, 4.72
(2H, d, OCH ₂ ), 6.92 to 7.07 (3H,
m, aromatic nucleus H), 7.32 (1H, t, aromatic nucleus H)

(2) 204 mg of the hydroxy compound (V) obtained in (1) above was dissolved in 0.3 ml of pyridine,
0.3 ml (6 equivalents) of acetic anhydride was added, and the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure and the residue was dissolved in 0.8 ml of tetrahydrofuran. 1,8-
Diazabicyclo [5.4.0] -7-undecene 0.4
3 ml (5 equivalents) was added, and the mixture was heated and stirred at 40 ° C. for 3.5 hours. After the reaction, 10 ml of diethyl ether was added to the reaction solution,
Extraction was performed by adding 3 ml of 1N hydrochloric acid. The ether layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- (3'-propargylstyryl-ONN-azoxy) -2,2-propylenedioxybutane (III
′) 130 mg was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.22 (3H, d, 4-CH ₃ ), 1.51 (3H,
s, 1-CH ₃ ), 2.54 (1H, t, ≡CH),
4.69 (1H, q, 3-CH-), 4.72 (2H,
_{d, OCH 2), 6.99~7.14 (} 3H, m, arom H), 7.33 (1H, t , arom H), 7.63
(1H, d = CH-), 7.77 (1H, d, -CH
=)

(3) 51 mg of the propargyl compound (III ') obtained in (2) above was dissolved in 1.5 ml of methanol, and 78 mg (2 equivalents) of iodine and 0.062 ml of 10N sodium hydroxide solution were added under ice cooling. In addition, the ice bath was removed and the mixture was stirred for 30 minutes. After the reaction, 0.5 ml of a 2N sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with diethyl ether. The ether layer was washed with 1N hydrochloric acid, saturated sodium hydrogen carbonate solution, and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3- [3 '-(3-iodopropargyloxy) styryl-ONN-azoxy] -2,2-.
60 mg of propylenedioxybutane (III) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.22 (3H, d, 4-CH ₃ ), 1.51 (3H,
_{s, 1-CH 3),} 4.70 (1H, q, 3-CH
-), 4.85 (2H, d , OCH 2), 6.97~
7.15 (3H, m, aromatic nucleus H), 7.33 (1H,
t, aromatic nucleus H), 7.63 (1H, d, = CH-),
7.77 (1H, d, -CH =)

(4) 110 mg of the propylenedioxy compound (III) obtained in (3) above is dissolved in 4 ml of acetone, 220 mg of ferric chloride-silica gel is added, and the mixture is stirred at room temperature for 2.5 hours. After the reaction, silica gel was removed, the mixture was diluted with diethyl ether, the ether layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. 3 ml of the residue was added to dimethylformamide-methanol (1: 5).
35 mg of hydroxylamine hydrochloride (1.5 mg)
Equivalent) and 0.05 ml of pyridine were added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the desired product (I).
52 mg of anti-isomer and 14 mg of syn-isomer were obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm anti-isomer 1.43 (3H, d, 4-CH ₃ ), 1.98 (3H,
_{s, 1-CH 3),} 4.85 (1H, q, 3-CH
-), 4.86 (2H, s , OCH 2), 6.97~
7.17 (3H, m, aromatic nucleus H), 7.34 (1H,
t, aromatic nucleus H), 7.57 (1H, d, 1 '= CH
-), 7.79 (1H, d , 2'-CH =) syn - isomer 1.47 (3H, d, 4- CH 3), 1.81 (3H,
_{s, 1-CH 3),} 4.86 (1H, q, 3-CH
-), 5.44 (2H, s , OCH 2), 6.98~
7.18 (3H, m, aromatic nucleus H), 7.34 (1H,
t, aromatic nucleus H), 7.58 (1H, d, 1 '= CH
-), 7.80 (1H, d, 2'-CH =)

Example 26 3- (3-Phenyl-1-propenyl-ONN-azoxy) -2-hydroxyiminobutane [Compound (I): R
₁ = benzyl group, R ₂ = R ₃ = hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) 376 obtained in Reference Example
mg was dissolved in 3 ml of tetrahydrofuran, cooled to −30 ° C., and stirred to obtain lithium diisopropylamide (1.3
Eq) hexane solution was added dropwise. After stirring for 30 minutes, 360 mg of phenylacetaldehyde (1.
3 ml of a tetrahydrofuran solution (5 equivalents) was added dropwise.
After the dropping, the mixture was stirred for another 50 minutes, and 3 ml of a saturated ammonium chloride solution was added to stop the reaction. The reaction solution was extracted with diethyl ether, and the ether layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, 3-
420 mg of the diastereomer of (2-hydroxy-3-phenylpropyl-ONN-azoxy) -2,2-propylenedioxybutane (V) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.15, 1.34 (3H, d, 4-CH ₃ ), 1.4
3,1.50 (3H, s, 1- CH 3), 1.90 (1
H, m), 2.71-2.85 (1H, m), 2.92
-3.05 (1H, m), 3.48-4.56 (7H,
m), 7.21 to 7.36 (5H, m, aromatic nucleus H)

(2) 278 mg of the hydroxy compound (V) obtained in (1) above was dissolved in 3 ml of pyridine, and 0.12 ml (2 equivalents) of methanesulfonyl chloride was added,
Stir at room temperature for 2 hours, then warm to 40 ° C. and stir overnight. After the reaction, the reaction solution was poured into ice water and extracted with diethyl ether. The ether layer was washed with a saturated sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- (3-phenyl-1-propenyl-O).
162 mg of NN-azoxy) -2,2-propylenedioxybutane (III) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.16 (3H, d, 4-CH ₃ ), 1.45 (3H,
_{s, 1-CH 3),} 3.53 (2H, dd, 3'-CH
_2- ), 3.86 to 3.98 (4H, m), 4.62
(1H, m, 3-CH-), 6.92 (1H, ddd,
1 '= CH-), 7.14 (1H, dd, 2'-CH
=), 7.16 to 7.36 (5H, m, aromatic nucleus H)

(3) 30 mg of the propylenedioxy compound (III) obtained in (2) above was dissolved in 2 ml of acetone, 60 mg of ferric chloride-silica gel was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, silica gel was removed, the mixture was diluted with diethyl ether, the ether layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in 1 ml of methanol and hydroxylamine hydrochloride 1
1.5 mg (1.5 equivalent) and 0.05 ml of pyridine were added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was concentrated under reduced pressure and purified by silica gel thin layer chromatography to obtain 13 mg of the anti-isomer and 7 mg of the syn-isomer of the target product (I). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm Anti-isomer (K-7489) 1.36 (3H, d, 4-CH ₃ ), 1.91 (3H,
_{s, 1-CH 3),} 3.53 (2H, d, 3'-CH 2
-), 4.78 (1H, q, 3-CH-), 6.86
(1H, m, 1 '= CH-), 7.10 to 7.38 (5
H, m, aromatic nucleus Hand olefinic H), 8.23
(1H, brs, OH) syn - isomer (K-7490) 1.10 (3H , d, 4-CH 3), 1.76 (3H,
_{s, 1-CH 3),} 3.54 (2H, d, 3'-CH 2
-), 5.36 (1H, q, 3-CH-), 6.90
(1H, m, 1'-CH-), 7.11 to 7.37 (6
H, m, aromatic nucleus Hand olefinic H), 8.06
(1H, brs, OH)

Example 27 3- [3- (2- (3-Iodopropargyloxy) phenyl) -1-propenyl-ONN-azoxy] -2-
Hydroxyiminobutane [Compound (I): R ₁ = 2-
(3-Iodopropargyloxy) -benzyl group, R ₂
= R ₃ = hydrogen atom]: (1) 3- (methyl-ONN-azoxy) -2,2-propylenedioxybutane (VI) 73 m obtained in Reference Example
g was dissolved in 1 ml of tetrahydrofuran, cooled to −30 ° C., and a hexane solution of lithium diisopropylamide (1.3 equivalents) was added dropwise with stirring. After stirring for 30 minutes,
88m of o-propargyloxybenzaldehyde
1 ml of a tetrahydrofuran solution of g (1.3 equivalents) was added dropwise. After the dropping, the mixture was stirred for additional 50 minutes, and 1 ml of a saturated ammonium chloride solution was added to stop the reaction. The reaction solution was extracted with diethyl ether, and the ether layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel and the diastereomer of 3- [2-hydroxy-3- (2-propargylphenyl) propyl-ONN-azoxy] -2,2-propylenedioxybutane (V). 94m
g was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.13, 1.23 (3H, d, 4-CH ₃ ), 1.4
2,1.49 (3H, s, 1- CH 3), 1.72~
2.03 (1H, m), 2.53 (1H, m), 2.8
6 to 3.04 (1H, m), 3.48 to 4.56 (7
H, m), 4.74 (2H , d, OCH 2), 6.94
~ 7.01 (2H, m, aromatic nucleus H), 7.21 to 7.2
8 (2H, m, aromatic nucleus H)

(2) The hydroxy compound (V) (94 mg) obtained in the above (1) was dissolved in pyridine (1 ml), and methanesulfonyl chloride (0.04 ml, 2 equivalents) was added.
Stir overnight at 0 ° C. After the reaction, the reaction solution was poured into ice water and extracted with diethyl ether. The ether layer was washed with a saturated sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography to give 3- [3- (2-propargyloxyphenyl) -1-propenyl-ONN-azoxy] -2,2-propylenedioxybutane (III ′) 5
0 mg was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.14 (3H, d, 4-CH ₃ ), 1.44 (3H,
s, 1-CH ₃ ), 3.50 (1H, t, ≡CH),
3.84 to 4.01 (4H, m), 4.62 (1H,
m, 3-CH-), 4.72 (2H, d, 1 '= CH
-), 6.88 (3H, m, 2'-CH = and aromatic nucleus H), 7.10 to 7.28 (3H, m, aromatic nucleus H)

(3) Dissolve 50 mg of the propargyl compound (III ') obtained in (2) above in methanol, add 90 mg (2 equivalents) of iodine and 0.07 ml (4 equivalents) of 10N sodium hydroxide solution, and add at room temperature. And stirred for 30 minutes. After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer is a 1N sodium thiosulfate solution,
The extract was washed with water and saturated saline, dried over Glauber's salt, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- [3- (2- (3-iodopropargyloxy) phenyl) -1-propenyl-ONN-azoxy] -2,2-propylenedioxybutane (III) 46m.
g was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.15 (3H, d, 4-CH ₃ ), 1.45 (3H,
_{s, 1-CH 3),} 1.53~1.68 (1H, m),
1.72-1.87 (1H, m), 3.52 (2H,
_{d, 3'-CH 2),} 3.84~4.01 (4H,
m), 4.62 (1H, q, 3-CH-), 4.85.
(2H, s, OCH ₂ ), 6.89 to 7.27 (6H,
m, aromatic nucleus and olefinic H)

(4) 28 mg of the propylenedioxy compound (III) obtained in (3) above was dissolved in 1 ml of acetone, 50 mg of ferric chloride-silica gel was added, and the mixture was stirred at room temperature for 4 hours. After the reaction, silica gel was removed, the mixture was diluted with diethyl ether, the ether layer was washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in 1 ml of methanol, and hydroxylamine hydrochloride was added.
5 mg (1.5 equivalent) and 0.05 ml of pyridine were added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was concentrated under reduced pressure and purified by silica gel thin layer chromatography to obtain 10 mg of a mixture of the target (I) anti-isomer and syn-isomer. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 1.35, 1.40 (3H, d, 4-CH ₃ ), 1.7
5,1.93 (3H, s, 1- CH 3), 3.54 (2
H, d, 3′-CH ₂ —), 4.88, 5.46 (1
H, q, 3-CH-), 4.95 (2H, s, OC
_{H 2), 6.85~7.09 (3H,} m, arom H),
7.11 to 7.29 (3H, m, aromatic nucleus Hand olefinic H)

Example 28 3- (1-Hexenyl-ONN-azoxy) -2- [2
-(3-iodopropargyloxy) benzoyloxyimino] -butane [Compound (I): R ₁ = n-butyl group, R ₂ = hydrogen atom, R ₃ = 2- (3-iodopropargyoxy) benzoyl group Preparation of 2- (3-iodopropargyloxy) -benzoic acid 302 mg was dissolved in 1 ml of dimethylformamide, 1 equivalent of 1,1′-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 20 minutes.
Add to this 3- (1-hexenyl-ONN-azoxy) -2
-Hydroxyiminobutane (2-hydroxyimino-2
-Deoxo-KA-7366A: PCT / JP / 010
82) A solution of 219 mg of dimethylformamide in 2 ml was added, and the mixture was stirred at 40 ° C. for 30 minutes. Then 1,8-
Diazabicyclo [5.4.0] -7-undecene 1.2
5 equivalents were added and further stirred for 2 hours. After the reaction, the mixture was diluted with 150 ml of diethyl ether, and the ether layer was washed successively with 0.5 N hydrochloric acid, saturated saline, saturated sodium hydrogen carbonate solution, saturated ammonium chloride solution, and saturated saline.
The organic solvent layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product (I). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 0.93 (3H, t, 6′-CH ₃ ), 1.30 to 1.
_{54 (4H, m, CH 2} -), 1.47 (3H, d, 4
_{-CH 3), 2.18 (3H,} s, 1-CH 3), 2.
22 (2H, q, 3'- CH 2 -), 4.92 (2H,
_{s, OCH 2), 5.06 (} 1H, q, 3-CH-),
6.95 (1H, d, 1 '= CH-), 7.01 (1
H, q, 2'-CH =), 7.08 (1H, t, aromatic nucleus H), 7.09 (1H, d, aromatic nucleus H), 7.51 (1
H, td, aromatic nucleus H), 7.87 (1H, dd, aromatic nucleus H)

Example 29 3- (1-Hexenyl-ONN-azoxy) -2- [3
-(3-Iodopropargyloxy) benzoyloxyimino] -butane [Compound (I): R ₁ = n-butyl group, R ₂ = hydrogen atom, R ₃ = 3- (3-iodopropargyloxy) benzoyl group] Production: 3- (3-iodopropargyloxy) -benzoic acid was used and treated in the same manner as in Example 28 to obtain the target product (I). ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 0.93 (3H, t, 6′-CH ₃ ), 1.31-1.
_{54 (4H, m, -CH 2} -), 1.49 (3H, d,
_{4-CH 3), 2.19 (} 3H, s, 1-CH 3),
2.23 (2H, q, 3'- CH 2 -), 4.89 (2
_{H, s, OCH 2),} 5.06 (1H, q, 3-CH
-), 6.96 (1H, d, 1 '= CH-), 7.02
(1H, q, 2'-CH =), 7.19 (1H, aromatic nucleus H), 7.40 (1H, aromatic nucleus H), 7.65 (1H,
Aromatic nucleus H), 7.77 (1H, aromatic nucleus H)

Example 30 3- (1-hexenyl-ONN-azoxy) -2 [4-
(3-iodopropargyloxy) benzoyloxyimino] -butane [Compound (I): R ₁ = n-butyl group,
R ₂ = hydrogen atom, R ₃ = 4- (3-iodo-propargyloxy) preparation of a benzoyl group]: 4- (3-iodo-propargyloxy) - objects react in the same manner as in Example 28 using benzoic acid The product (I) was obtained. ¹ H-NMR value: δ CDCl ₃ , TMS, ppm 0.98 (3H, t, 6′-CH ₃ ), 1.30 to 1.
_{54 (4H, m, -CH 2} -), 1.47 (3H, d,
_{4-CH 3), 2.18 (} 3H, s, 1-CH 3),
2.23 (2H, q, 3'- CH 2 -), 4.89 (2
_{H, s, OCH 2),} 5.06 (1H, q, 3-CH
-), 6.95 (1H, d, 1 '= CH-) 7.01
(2H, t, aromatic nucleus H), 7.03 (1H, q, 2'-
CH =), 8.04 (2H, d, aromatic nucleus H)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroyuki Ishiwata 1-8-3 Sugano, Ichikawa City, Chiba Prefecture (72) Inventor Yukihiro Okuno 2-17-43 Noguchi Town, Higashimurayama City, Tokyo Hisashi Ito 461 Imafuku, Kawagoe-shi, Saitama Prefecture 461 Denen Heights Kawagoe 2-205 (72) Inventor Shozo Shirato 4-43-2 Shimobori, Musashimurayama-shi, Tokyo

Claims (4)

[Claims] [Claim 1] [In the formula, R ₁ and R ₂ are the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group (which may be substituted with a halogen atom). , A lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group (which may be substituted with a halogen atom),
An aryl group or an aralkyl group (the aryl group and the aralkyl group may be substituted with 1 to 2 halogen atoms, a lower alkyl group, a lower alkoxy group, a halogenated lower alkynyl group or a halogenated lower alkynyloxy group), R ₃ is a hydrogen atom, a lower alkyl group (which may be substituted with a carboxyl group), a lower alkynyl group (which may be substituted with a halogen atom), a lower alkynyloxy group (which may be substituted with a halogen atom) ), A benzoyl group (which may be substituted with a halogenated lower alkynyloxy group), but when R ₁ represents an n-butyl group, R ₃ represents a halogenated lower alkynyl group or a halogenated alkynyloxy group. A substituted benzoyl group]. 2. A compound according to claim 1 which is an anti-isomer of a compound of general formula I. 3. A compound according to claim 1, which is a syn-isomer of the compound of general formula I. 4. An antifungal agent containing the compound according to claim 1 as an active ingredient.